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Сергеева Марина Глебовна, нии фхб им. А. Н. Белозерского мгу e-mail: Москва, 2008 Оглавление тезисы

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DAF

P08174

 CD55

 

 This protein recognizes C4b and C3b fragments that condense with cell-surface hydroxyl or amino groups when nascent C4b and C3b are locally generated during C4 and c3 activation. Interaction of daf with cell-associated C4b and C3b polypeptides interferes with their ability to catalyze the conversion of C2 and factor B to enzymatically active C2a and Bb and thereby prevents the formation of C4b2a and C3bBb, the amplification convertases of the complement cascade.

Also acts as the receptor for echovirus 7 and related viruses




plasma membranes, surfaces of epithelial cells, body fluids and in extracellular matrix

receptors of complement activation (RCA)

DHC24

Q15392

 DHCR24

 Defects in DHCR24 are the cause of desmosterolosis [MIM:602398]. It is a rare autosomal recessive disorder characterized by multiple congenital anomalies and elevated levels of the cholesterol precursor desmosterol in plasma, tissue, and cultured cells.

 Catalyzes the reduction of the delta-24 double bond of sterol intermediates. Protects cells from oxidative stress by reducing caspase 3 activity during apoptosis induced by oxidative stress. Also protects against amyloid-beta peptide-induced apoptosis.

Сщафсещк - FAD.

In brains affected by Alzheimer disease, expression in the inferior temporal lobe is substantially lower than in the frontal cortex.

brain and adrenal gland, liver, lung, spleen, prostate and spinal cord, heart, uterus and prostate, In the brain, strongly expressed in cortical regions, substantia nigra, caudate nucleus, hippocampus, medulla oblongata and pons

FAD-binding oxidoreductase/transferase type 4

DOCK3

Q81ZD9

 DOCK3

 Alzheimer

 Potential guanine nucleotide exchange factor (GEF). GEF proteins activate some small GTPases by exchanging bound GDP for free GTP. Its interaction with presenilin proteins as well as its ability to stimulate Tau/MAPT phosphorylation suggest that it may be involved in Alzheimer disease. Ectopic expression in nerve cells decreases the secretion of beta-amyloid APBA1 protein and lowers the rate of cell-substratum adhesion, suggesting that it may affect the function of some small GTPase involved in the regulation of actin cytoskeleton or cell adhesion receptors (By similarity).

Interacts with presenilin proteins PSEN1 and PSEN2. Interacts with CRK (By similarity). In normal brains, it is localized in the neuropil, and occasionally in the pyramidal cells, while in Alzheimer disease brains, it is associated with neurofibrillary tangles.

brains



DOCK

DPYL2

Q16555

 DPYSL2

 AD

 Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance, neuronal growth cone collapse and cell migration (By similarity).

3F4, a monoclonal antibody which strongly stains neurofibrillary tangles in Alzheimer disease brains, specifically labels DPYSL2 when phosphorylated on Ser-518, Ser-522 and Thr-509.

Ubiquitous

DHOase

ECE2

O60344

ECE2

 AD

 Converts big endothelin-1 to endothelin-1. Also involved in the processing of various neuroendocrine peptides, including neurotensin, angiotensin I, substance P, proenkephalin-derived peptides, and prodynorphin-derived peptides. May limit beta- amyloid peptide accumulation in brain. May also have methyltransferase activity.

Strongly down-regulated in inferior parietal lobe from Alzheimer disase patients (at protein level).

brain

methyltransferase super, peptidase M13

EI2BB

P49770

EIF2B2 

 Leukoencephalopathy with vanishing white matter (VWM), ovarioleukodystrophy

Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP.







EIF-2B alpha/beta/delta subunits

EST1

P23141

 CES1

 

 Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acyl CoA ester.




liver with lower levels in heart and lung

type-B carboxylesterase/lipase

FA38A

Q92508

FAM38A 

 AD, PD

 Endoplasmic reticulum membrane; Multi-pass membrane protein. Endoplasmic reticulum-Golgi intermediate compartment membrane (By similarity).

In Alzheimer disease brains, expressed in about half of the activated astrocytes located around classical senile plaques. In Parkinson disease substantia nigra, not detected in melanin-containing neurons nor in activated astrocytes.

In normal brain, expressed exclusively in neurons, not in astrocytes.

FAM38

FHL2

Q14192

FHL2 

 

 Interacts with ZNF638 and TTN/titin. Contains 4 LIM zinc-binding domains.




skeletal muscle and heart




FLNB

O75369

 FLNB

 Interaction with FLNA may compensate for dysfunctional FLNA homodimer in the periventricular nodular heterotopia (PVNH) disorder.

Defects in FLNB are the cause of atelosteogenesis type 1 (AO1) [MIM:108720]; also known as giant cell chondrodysplasia or spondylohumerofemoral hypoplasia. Atelosteogenesis are lethal short-limb skeletal dysplasias with vertebral abnormalities, disharmonious skeletal maturation, poorly modeled long bones and joint dislocations.

Defects in FLNB are the cause of atelosteogenesis type 3 (AO3) [MIM:108721]. Atelosteogenesis are short-limb lethal skeletal dysplasias with vertebral abnormalities, disharmonious skeletal maturation, poorly modeled long bones and joint dislocations. In AO3 recurrent respiratory insufficiency and/or infections usually result in early death.

Defects in FLNB are the cause of boomerang dysplasia [MIM:112310]. This is a perinatal lethal osteochondrodysplasia characterized by absence or underossification of the limb bones and vertebre. Boomerang dysplasia is distinguished from atelosteogenesis on the basis of a more severe defect in mineralisation, with complete absence of ossification in some limb elements and vertebral segments.

Defects in FLNB are the cause of autosomal dominant Larsen syndrome (LRS1) [MIM:150250]. LRS1 is a genetically heterogeneous disorder characterized by multiple joint dislocations, craniofacial abnormalities and accessory carpal bones.

Defects in FLNB are the cause of spondylocarpotarsal synostosis syndrome [MIM:272460]; also known as spondylocarpotarsal syndrome (SCT) or congenital synspondylism or vertebral fusion with carpal coalition or congenital scoliosis with unilateral unsegmented bar. The disorder is characterized by short stature and vertebral, carpal and tarsal fusions.

 Connects cell membrane constituents to the actin cytoskeleton. May promote orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. Anchors various transmembrane proteins to the actin cytoskeleton. Interaction with FLNA may allow neuroblast migration from the ventricular zone into the cortical plate. Various interactions and localizations of isoforms affect myotube morphology and myogenesis. Isoform 6 accelerates muscle differentiation in vitro.

Also expressed in thyroid adenoma, neurofibrillary tangles (NFT), senile plaques in the hippocampus and cerebral cortex in Alzheimer disease (AD).

Iso 1, 2 - in placenta, bone marrow, brain, umbilical vein endothelial cells (HUVEC), retina and skeletal muscle. Iso in prostate, uterus, liver, thyroid, stomach, lymph node, small intestine, spleen, skeletal muscle, kidney, placenta, pancreas, heart, lung, platelets, endothelial cells, megakaryocytic and erythroleukemic cell lines. Iso 2 in spinal cord, platelet and Daudi cells. Iso 3 , 6 in lung, heart, skeletal muscle, testis, spleen, thymus and leukocytes. Iso 4, 5 in heart.

filamin

FOLH1

Q04609

 FOLH1

 AD

 Has both folate hydrolase and N-acetylated-alpha-linked- acidic dipeptidase (NAALADase) activity. Has a preference for tri- alpha-glutamate peptides. In the intestine, required for the uptake of folate. In the brain, modulates excitatory neurotransmission through the hydrolysis of the neuropeptide, N- aceylaspartylglutamate (NAAG), thereby releasing glutamate. Isoforms PSM-4 and PSM-5 would appear to be physiologically irrelevant. Involved in prostate tumor progression.

Also exhibits a dipeptidyl-peptidase IV type activity. In vitro, cleaves Gly-Pro-AMC.

Genetic variation in FOLH1 may be associated with low folate levels and consequent hyperhomocysteinemia. This condition can result in increased risk of cardiovascular disease, neural tube defects, and cognitive deficits.

PSMA is used as a diagnostic and prognostic indicator of prostate cancer, and as a possible marker for various neurological disorders such as schizophrenia, Alzheimer disease and Huntington disease.

Highly expressed in prostate epithelium. Also expressed, in the small intestine, brain, kidney, liver, spleen, colon, trachea, spinal cord and the capillary endothelium of a variety of tumors. Expressed specifically in jejunum brush border membranes. In the brain, highly expressed in the ventral striatum and brain stem. Also expressed in fetal liver and kidney. In the prostate, the PSMA' cytosolic isoform is the most abundant form in normal tissue, the membrane-bound PSMA-1 form in primary prostate tumors. The PSMA-2 isoform also found in normal prostate as well as in brain and liver.

peptidase M28, M28B sub

FRIH

P02794

 FTH1

 

 Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Has ferroxidase activity. Iron is taken up in the ferrous form and deposited as ferric hydroxides after oxidation.







ferritin

GFAP

P14134

 GFAP

 Defects in GFAP are a cause of Alexander disease [MIM:203450]. Alexander disease is a rare disorder of the central nervous system. It is a progressive leukoencephalopathy whose hallmark is the widespread accumulation of Rosenthal fibers which are cytoplasmic inclusions in astrocytes. The most common form affects infants and young children, and is characterized by progressive failure of central myelination, usually leading to death usually within the first decade. Infants with Alexander disease develop a leukoencephalopathy with macrocephaly, seizures, and psychomotor retardation. Patients with juvenile or adult forms typically experience ataxia, bulbar signs and spasticity, and a more slowly progressive course.

GFAP, a class-III intermediate filament, is a cell- specific marker that, during the development of the central nervous system, distinguishes astrocytes from other glial cells.

Isoform 3 interacts with N-terminus of PSEN1.

cells lacking fibronectin

intermediate filament

HCD2

Q99714

 HSD17B10

 AD

 Binds intracellular amyloid-beta. By interacting with amyloid-beta, it may contribute to the neuronal dysfunction associated with Alzheimer disease (AD).

Defects in HSD17B10 are the cause of 2-methyl-3- hydroxybutyryl-CoA dehydrogenase deficiency (MHBD deficiency) [MIM:300438]. MHBD deficiency leads to neurological abnormalities, including psychomotor retardation, and, in virtually all patients, loss of mental and motor skills.

Defects in HSD17B10 are the cause of X-linked syndromic mental retardation type 10 (MRXS10) [MIM:300220]. MRXS10 is characterized by mild mental retardation, choreoathetosis and abnormal behavior.




normal tissues but is overexpressed in neurons affected in AD

short-chain dehydrogenases/reductases (SDR)

HERP1

Q15011

 HERPUD1

 AD

 Component of the endoplasmic reticulum quality control (ERQC) system also called ER-associated degradation (ERAD) involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins. Could enhance presenilin-mediated beta-amyloid protein 40 generation.

Interacts with PSEN1 and PSEN2. Interacts with SYVN1 Present in activated microglia in senile plaques in the brain of patients with Alzheimer disease..

in the brain, expression seems to be restricted to neurons and vascular smooth muscle cells.

Contains 1 ubiquitin-like domain.

HRH2

P25021

 HRH2

 

 The H2 subclass of histamine receptors mediates gastric acid secretion. Also appears to regulate gastrointestinal motility and intestinal secretion. Possible role in regulating cell growth and differentiation. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and, through a separate G protein-dependent mechanism, the phosphoinositide/protein kinase (PKC) signaling pathway (By similarity).

Antagonists for this receptor have proven to be effective therapy for acid peptic disorders of the gastrointestinal tract. Certain antagonists are used in the treatment of neuropsychiatric and neurological diseases such as schizophrenia, Alzheimer disease and Parkinson disease.






G-protein coupled receptor 1

HUNIN

Q81VG9

 HN

 AD

 Plays a role as a neuroprotective factor against death induced by multiple different types of familial Alzheimer disease genes and beta amyloid in Alzheimer disease. Induced chemotaxis of mononuclear phagocytes by using FPRL1. Reduced the aggregation and fibrillary formation by suppressing the effect of APP on mononuclear phagocytes and acts by competitively inhibiting the access of FPRL1 to APP. Prevents the translocation of BAX from cytosol to mitochondria.




Expressed in the heart, skeletal muscles, kidney and liver. Lesser but significant expression is observed in the brain and the gastrointestinal tract. Expressed in the AD brain, where it is found in some of the large intact neurons of the occipital lobes and small and round reactive glial cells in the hippocampus.




IBP3

P17936

 IGFBP3

 

 IGF-binding proteins prolong the half-life of the IGFs and have been shown to either inhibit or stimulate the growth promoting effects of the IGFs on cell culture. They alter the interaction of IGFs with their cell surface receptors.

IGFBP3 levels increase in the presence of IGF1, insulin and other growth-stimulating factors such as growth hormone, epidermal growth factor, and phorbol esters.




most tissues

Contains 1 IGFBP N-terminal domain.

1 thyroglobulin type-1 domain

ITM2B

Q9Y287

ITM2B 

 Defects in ITM2B may be associated with familial British dementia (FBD) [MIM:176500]. FBD is an autosomal dominant disease characterized by progressive dementia, spasticity, and cerebellar ataxia, with onset at around the fifth decade of life. Cerebral amyloid angiopathy, non-neuritic and perivascular plaques and neurofibrillary tangles are the predominant pathological lesions.


 The amyloid peptides ABri and ADan are probably proteolytically derived by a furin-like enzyme. The amyloid fibrils cause neuronal dysfunction and dementia.

Defects in ITM2B may be associated with familial Danish dementia (FDD) [MIM:117300]; also known as heredopathia ophthalmo- oto-encephalica. FDD is an autosomal dominant disorder characterized by cataracts, deafness, progressive ataxia, and dementia. Neuropathological findings include severe widespread cerebral amyloid angiopathy, hippocampal plaques, and neurofibrillary tangles, similar to Alzheimer disease.

brain and in other tissues

ITM2

JIP1

Q9UQF2

 MAPK8IP1

 Defects in MAPK8IP1 are a cause of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:125853]. NIDDM is characterized by an autosomal dominant mode of inheritance, onset during adulthood and insulin resistance.

 The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. Required for JNK activation in response to excitotoxic stress. Cytoplasmic MAPK8IP1 causes inhibition of JNK- regulated activity by retaining JNK in the cytoplasm and inhibiting JNK phosphorylation of c-Jun. May also participate in ApoER2-specific reelin signaling. Directly, or indirectly, regulates GLUT2 gene expression and beta-cell function. Appears to have a role in cell signaling in mature and developing nerve terminals. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins (By similarity). Functions as an anti-apoptotic protein and whose level seems to influence the beta-cell death or survival response.

Binds the TPR motif-containing C-terminal of KNS2, then the pre-assembled MAPK8IP1 scaffolding complexes are transported as a cargo of kinesin, to the required subcellular location. Interacts with the cytoplasmic domain of APP (By similarity).

Expressed in neurons, localizing to neurite tips in differentiating cells. Also expressed in the pancreas, testis and prostate. Low levels in heart, ovary and small intestine. Decreased levels in pancreatic beta cells sensitize cells to IL-1-beta-induced apoptosis.

brain

JIP scaffold

KLK6

Q92876

KLK6

 

 




brain. Also found in colon and kidney.

peptidase S1 family. Kallikrein sub


KLK8

O60259

 

 Expressed at high levels in serum, ascites fluid and tumor cytosol of advanced stage ovarian cancer patients and may serve as a marker of ovarian cancer.

Serine protease which is capable of degrading a number of proteins such as casein, fibrinogen, kininogen, fibronectin and collagen type IV. Also cleaves L1CAM in response to increased neural activity. Induces neurite outgrowth and fasciculation of cultured hippocampal neurons. Plays a role in the formation and maturation of orphan and small synaptic boutons in the Schaffer- collateral pathway, regulates Schaffer-collateral long-term potentiation in the hippocampus and is required for memory acquisition and synaptic plasticity. Involved in skin desquamation and keratinocyte proliferation. Plays a role in the secondary phase of pathogenesis following spinal cord injury.




Isoform 1 is predominantly expressed in the pancreas while isoform 2 is expressed in adult brain and hippocampus. Both forms are also found in fetal brain and placenta. Detected in salivary gland, uterus, thymus, breast, testis and kidney but not in spleen, liver, lung or normal ovarian tissue. Displays an 11.5-fold increase in Alzheimer disease hippocampus compared to controls and is overexpressed in some ovarian carcinomas. Expressed at low levels in normal skin while high levels are found in psoriasis vulgaris, seborrheic keratosis, lichen planus and squamous cell carcinoma skin samples.

peptidase S1 family. Kallikrein subfamily

LRP8

Q14114

 

 Genetic variation in LRP8 is associated with susceptibility to myocardial infarction type 1 [MIM:608446]. Atherosclerotic coronary artery disease (CAD) and myocardial infarction (MI) are complex traits that account for the leading cause of death in the Western world heart disease.

 Cell surface receptor for Reelin (RELN) and apolipoprotein E (apoE)-containing ligands. LRP8 participates in transmitting the extracellular Reelin signal to intracellular signaling processes, by binding to DAB1 on its cytoplasmic tail. Reelin acts via both the VLDL receptor (VLDLR) and LRP8 to regulate DAB1 tyrosine phosphorylation and microtubule function in neurons. LRP8 has higher affinity for Reelin than VLDLR. LRP8 is thus a key component of the Reelin pathway which governs neuronal layering of the forebrain during embryonic brain development. Binds the endoplasmic reticulum resident receptor-associated protein (RAP). Binds dimers of beta 2-glycoprotein I and may be involved in the suppression of platelet aggregation in the vasculature. Highly expressed in the initial segment of the epididymis, where it affects the functional expression of clusterin and phospholipid hydroperoxide glutathione peroxidase (PHGPx), two proteins required for sperm maturation. May also function as an endocytic receptor.




Expressed mainly in brain and placenta. Also expressed in platelets and megakaryocytic cells. Not expressed in the liver.

LDLR

LRRK2

Q5S007

 

 Defects in LRRK2 are the cause of Parkinson disease 8 (PARK8) [MIM:607060, 168600]. Parkinson disease (PD) is a complex, multifactorial disorder that typically manifests after the age of 50 years, although early-onset cases (before 50 years) are known. PD generally arises as a sporadic condition but is occasionally inherited as a simple mendelian trait. Although sporadic and familial PD are very similar, inherited forms of the disease usually begin at earlier ages and are associated with atypical clinical features. PD is characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. PARK8 is an autosomal-dominant late- onset parkinsonism, characterized by onset from 50 to 65 years, with slow progression and relatively benign course.

 Probable protein kinase whose role is not yet known. May play a role in the phosphorylation of proteins central to Parkinson disease. May also have GTPase activity.




Expressed throughout the adult brain, but at a lower level than in heart and liver. Also expressed in placenta, lung, skeletal muscle, kidney and pancreas. In the brain, expressed in the cerebellum, cerebral cortex, medulla, spinal cord occipital pole, frontal lobe, temporal lobe and putamen. Expression is particularly high in brain dopaminoceptive areas.

protein kinase superfamily. TKL Ser/Thr protein kinase

MADD

Q8WXG6

 

 Overexpression of MADD activates the mitogen- activated protein (MAP) kinase extracellular signal-regulated kinase (ERK). Expression of the MADD death domain stimulates both the ERK and c-JUN N-terminal kinase MAP kinases and induces the phosphorylation of cytosolic phospholipase A2.

 Plays a significant role in regulating cell proliferation, survival and death through alternative mRNA splicing. Isoform 5 shows increased cell proliferation and isoform 2 shows decreased. Converts GDP-bound inactive form of RAB3A, RAB3C and RAB3D to the GTP-bound active forms. Component of the TNFRSF1A signaling complex: MADD links TNFRSF1A with MAP kinase activation. Plays an important regulatory role in physiological cell death (TNF-alpha-induced, caspase-mediated apoptosis); isoform 1 is susceptible to inducing apoptosis, isoform 5 is resistant and isoform 3 and isoform 4 have no effect.




Highly expressed in fetal brain and kidney; adult testis, ovary, brain and heart. Isoform 5 is constitutively expressed in all tissues. Isoform 7 is expressed in fetal liver and in several cancer cell lines.

MADD

MAP2

P11137

 

 

 










MAZ

P56270

 

 

 May function as a transcription factor with dual roles in transcription initiation and termination. Binds to two sites, ME1a1 and ME1a2, within the c-myc promoter having greater affinity for the former. Also binds to multiple G/C-rich sites within the promoter of the Sp1 family of transcription factors.

Interacts with BPTF.

Nucleus (Probable). Note=In brains of Alzheimer disease patients, present in a plaque-like structures.

Present in kidney, liver and brain. In the brain, highest levels are found in motor cortex and midfrontal cortex (at protein level).

Contains 6 C2H2-type zinc fingers

MEPD

P52888

 

 

 










MLH3

Q9UHC1

 

 Defects in MLH3 are the cause of hereditary non-polyposis colorectal cancer type 7 (HNPCC7) [MIM:604395]. Mutations in more than one gene locus can be involved alone or in combination in the production of the HNPCC phenotype (also called Lynch syndrome). Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2 genes. HNPCC is an autosomal, dominantly inherited disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early onset colorectal carcinoma (CRC) and extra-colonic cancers of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world, and accounts for 15% of all colon cancers. Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Clinically, HNPCC is often divided into two subgroups. Type I: hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II: patients have an increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term "suspected HNPCC" or "incomplete HNPCC" can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected.

Defects in MLH3 are a cause of somatic colorectal cancer (CRC) [MIM:114500].

 Probably involved in the repair of mismatches in DNA.




Ubiquitous.

DNA mismatch repair mutL/hexB

MT2

P02795

 MT2A

 

 Metallothioneins have a high content of cysteine residues that bind various heavy metals; these proteins are transcriptionally regulated by both heavy metals and glucocorticoids.

This metallothionein binds zinc.







metallothionein superfamily. Type 1 family

MT3

P25713

 

 

 Binds heavy metals. Contains three zinc and three copper atoms per polypeptide chain and only a negligible amount of cadmium. Inhibits survival and neurite formation of cortical neurons in vitro.

Abundant in a subset of astrocytes in the normal human brain, but greatly reduced in the Alzheimer disease (AD) brain.

brain

metallothionein superfamily. Type 1 family.

NCKP1

Q9YA27

NCKAP1

 

 Is part of lamellipodial complex that controls Rac- dependent actin remodeling (By similarity).




Expressed in all tissues examined except peripheral blood leukocytes, with highest expression in brain, heart, and skeletal muscle.

HEM-1/HEM-2



NDRG2

Q9UN36

 

 Not expressed or strongly down-regulated in various cancer types, such as astrocytoma, meningioma, liver cancer and pancreatic cancer.

Found in pathological brain lesions of Alzheimer disease.

 May be involved in dendritic cell and neuron differentiation. May have anti-tumor activity.

Isoforms 1 and 2 are present in brain neurons and up-regulated in Alzheimer disease (at protein level).

brain, heart, skeletal muscle and salivary gland, and kidney and liver, dendritic cells, but not in other blood cells.

NDRG



NEUG

Q92686

 NRGN

 

 Acts as a "third messenger" substrate of protein kinase C-mediated molecular cascades during synaptic development and remodeling. Binds to calmodulin in the absence of calcium (By similarity).







neurogranin

NU1M

P03886

 MT-ND1

 Defects in MT-ND1 are a cause of Leber hereditary optic neuropathy (LHON) [MIM:535000]; also known as Leber optic atrophy. LHON is a maternally inherited disease resulting in acute bilateral blindness due to retinal degeneration predominantly in young men. Cardiac conduction defects and neurological defects have also been described, resulting in optic nerve degeneration and cardiac dysrhythmia.

Defects in MT-ND1 are a cause of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome (MELAS) [MIM:540000]. MELAS is a genetically heterogenious disorder, characterized by episodic vomiting, seizures, and recurrent cerebral insults resembling strokes and causing hemiparesis, hemianopsia, or cortical blindness.

Defects in MT-ND1 may be associated with non-insulin- dependent diabetes mellitus (NIDDM).

 Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) that is believed to belong to the minimal assembly required for catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone (By similarity).

Defects in MT-ND1 may be associated with mitochondrial susceptibility to Alzheimer disease (AD) [MIM:502500].




complex I subunit 1

NU2M

P03891

 MT-ND2

 Defects in MT-ND2 are a cause of Leber hereditary optic neuropathy (LHON) [MIM:535000]; also known as Leber optic atrophy. LHON is a maternally inherited disease resulting in acute bilateral blindness due to retinal degeneration predominantly in young men. Cardiac conduction defects and neurological defects have also been described, resulting in optic nerve degeneration and cardiac dysrhythmia.


 Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) that is believed to belong to the minimal assembly required for catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone (By similarity).

Defects in MT-ND2 may be associated with mitochondrial susceptibility to Alzheimer disease (AD) [MIM:502500].






complex I subunit 2

NUMB

P49757

 

 

 Implicated in the control of cell fate decisions during development.

Isoform 1 and isoform 2 are ubiquitinated by LNX leading to their subsequent proteasomal degradation (By similarity). Ubiquitinated; mediated by SIAH1 and leading to its subsequent proteasomal degradation.







Contains 1 PID domain.

OLR1

P78380

 

 Defects in OLR1 may be a cause of susceptibility to myocardial infarction [MIM:608557].

 Receptor that mediates the recognition, internalization and degradation of oxidatively modified low density lipoprotein (oxLDL) by vascular endothelial cells. OxLDL is a marker of atherosclerosis that induces vascular endothelial cell activation and dysfunction, resulting in pro-inflammatory responses, pro- oxidative conditions and apoptosis. Its association with oxLDL induces the activation of NF-kappa-B through an increased production of intracellular reactive oxygen and a variety of pro- atherogenic cellular responses including a reduction of nitric oxide (NO) release, monocyte adhesion and apoptosis. In addition to binding oxLDL, it acts as a receptor for the HSP70 protein involved in antigen cross-presentation to naive T-cells in dendritic cells, thereby participating in cell-mediated antigen cross-presentation. Also involved in inflammatory process, by acting as a leukocyte-adhesion molecule at the vascular interface in endotoxin-induced inflammation. Also acts as a receptor for advanced glycation end (AGE) products, activated platelets, monocytes, apoptotic cells and both Gram-negative and Gram- positive bacteria.

Defects in OLR1 may be associated with susceptibility to Alzheimer disease (AD) [MIM:104300]. Involvement in AD is however unclear: according to some authors (Ref.10, Ref.13 and Ref.18), variations in OLR1 modify the risk of AD, while according to other (Ref.15 and Ref.16), they do not.

Expressed at high level in endothelial cells and vascular-rich organs such as placenta, lung, liver and brain, aortic intima, bone marrow, spinal cord and substantia nigra. Also expressed at the surface of dendritic cells. Widely expressed at intermediate and low level.

Contains 1 C-type lectin domain.

PAWR

Q96IZ0

 

 

 Pro-apoptopic protein capable of selectively inducing apoptosis in cancer cells, sensitizing the cells to diverse apoptotic stimuli and causing regression of tumors in animal models. Induces apoptosis in certain cancer cells by activation of the Fas prodeath pathway and coparallel inhibition of NF-kappa-B transcriptional activity. Inhibits the transcriptional activation and augments the transcriptional repression mediated by WT1. Down- regulates the anti-apoptotic protein BCL2 via its interaction with WT1. Seems also to be a transcriptional repressor by itself. May be directly involved in regulating the amyloid precursor protein (APP) cleavage activity of BACE1.

Interacts with WT1, via the C-terminal region. Homooligomer. Interacts also with a wide variety of proteins, such as atypical PKCs, p62, DAPK3 kinase and THAP1. Interacts with actin, AATF, BACE1, SPSB1, SPSB2 AND SPSB4. Component of a ternary complex composed of SQSTM1 and PRKCZ.

Widely expressed. Expression is elevated in various neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer, Parkinson and Huntington diseases and stroke. Down-regulated in several cancers.




PCSK1

Q9UHG2

 PCSK1N

 

 May function in the control of the neuroendocrine secretory pathway. Proposed be a specific endogenous inhibitor of PCSK1. ProSAAS and Big PEN-LEN, both containing the C-terminal inhibitory domain, but not the further processed peptides reduce PCSK1 activity in the endoplasmic reticulum and Golgi. It reduces the activity of the 84 kDa form but not the autocatalytically derived 66 kDa form of PCSK1. Subsequent processing of proSAAS may eliminate the inhibition. Slows down convertase-mediated processing of proopiomelanocortin and proenkephalin. May control the intracellular timing of PCSK1 rather than its total level of activity. The function of the processed secreted peptides is not known (By similarity).

Secreted (By similarity). Golgi apparatus, trans-Golgi network (By similarity). Note=A N-terminal processed peptide, probably Big SAAS or Little SAAS, is accumulated in cytoplasmic protein tau deposits in frontotemporal dementia and parkinsonism linked to chromosome 17 (Pick disease), Alzheimer disease and amyotrophic lateral sclerosis-parkinsonism/dementia complex 1 (Guam disease).

Expressed in brain and pancreas.




PIMT

P22061

PCMT1 

 

 Catalyzes the methyl esterification of L-isoaspartyl and D-aspartyl residues in peptides and proteins that result from spontaneous decomposition of normal L-aspartyl and L-asparaginyl residues. It plays a role in the repair and/or degradation of damaged proteins. Acts on microtubule-associated protein 2, calreticulin, clathrin light chains a and b, Ubiquitin carboxyl- terminal hydrolase isozyme L1, phosphatidylethanolamine-binding protein 1, stathmin, beta-synuclein and alpha-synuclein (By similarity).







L-isoaspartyl/D-aspartyl protein methyltransferase

PREP

Q5JRX3

PITRM1 

 

 ATP-independent protease that degrades mitochondrial transit peptides after their cleavage. Also degrades other unstructured peptides. Specific for peptides in the range of 10 to 65 residues. Able to degrade amyloid beta A4 (APP) protein when it accumulates in mitochondrion, suggesting a link with Alzheimer disease. Shows a preference for cleavage after small polar residues and before basic residues, but without any positional preference.




muscle and heart, brain, pancreas, liver, lung and placenta

peptidase M16 family. PreP subfamily

PRIO

P04156

 PRNP

 PrP is found in high quantity in the brain of humans and animals infected with neurodegenerative diseases known as transmissible spongiform encephalopathies or prion diseases, like: Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), Gerstmann-Straussler disease (GSD), Huntington disease-like 1 (HDL1) and kuru in humans; scrapie in sheep and goat; bovine spongiform encephalopathy (BSE) in cattle; transmissible mink encephalopathy (TME); chronic wasting disease (CWD) of mule deer and elk; feline spongiform encephalopathy (FSE) in cats and exotic ungulate encephalopathy (EUE) in nyala and greater kudu. The prion diseases illustrate three manifestations of CNS degeneration: (1) infectious (2) sporadic and (3) dominantly inherited forms. TME, CWD, BSE, FSE, EUE are all thought to occur after consumption of prion-infected foodstuffs.

Defects in PRNP are the cause of Creutzfeldt-Jakob disease (CJD) [MIM:123400]. CJD occurs primarily as a sporadic disorder (1 per million), while 10-15% are familial. Accidental transmission of CJD to humans appears to be iatrogenic (contaminated human growth hormone (HGH), corneal transplantation, electroencephalographic electrode implantation, etc.). Epidemiologic studies have failed to implicate the ingestion of infected annimal meat in the pathogenesis of CJD in human. The triad of microscopic features that characterize the prion diseases consists of (1) spongiform degeneration of neurons, (2) severe astrocytic gliosis that often appears to be out of proportion to the degree of nerve cell loss, and (3) amyloid plaque formation. CJD is characterized by progressive dementia and myoclonic seizures, affecting adults in mid-life. Some patients present sleep disorders, abnormalities of high cortical function, cerebellar and corticospinal disturbances. The disease ends in death after a 3-12 months illness.

Defects in PRNP are the cause of fatal familial insomnia (FFI) [MIM:600072]. FFI is an autosomal dominant disorder and is characterized by neuronal degeneration limited to selected thalamic nuclei and progressive insomnia.

Defects in PRNP are the cause of Gerstmann-Straussler disease (GSD) [MIM:137440]. GSD is a heterogeneous disorder and was defined as a spinocerebellar ataxia with dementia and plaquelike deposits. GSD incidence is less than 2 per 100 million live births.

Defects in PRNP are the cause of Huntington disease-like 1 (HDL1) [MIM:603218]. HDL1 is an autosomal dominant, early onset neurodegenerative disorder with prominent psychiatric features.

Defects in PRNP are the cause of kuru [MIM:245300]. Kuru is transmitted during ritualistic cannibalism, among natives of the New Guinea highlands. Patients exhibit various movement disorders like cerebellar abnormalities, rigidity of the limbs, and clonus. Emotional lability is present, and dementia is conspicuously absent. Death usually occurs from 3 to 12 month after onset.

Defects in PRNP are the cause of prion disease with protracted course [MIM:606688]; an autosomal dominant presenile dementia with a rapidly progressive and protracted clinical course. The dementia was characterized clinically by frontotemporal features, including early personality changes. Some patients had memory loss, several showed aggressiveness, hyperorality and verbal stereotypy, others had parkinsonian symptoms.


 The physiological function of PrP is not known.







prion

PRND

Q9UKYO

 

 

 Not known.




testis

prion

PSMD4

P55036

 

 

 Binds and presumably selects ubiquitin-conjugates for destruction. Displays selectivity for longer polyubiquitin chains. Modulates intestinal fluid secretion.

The 2 UIM motifs are involved in the binding to a multi- ubiquitin chain in a cooperative way.







proteasome subunit S5A

PSN1

P49768

 PSEN1

 Defects in PSEN1 are a cause of frontotemporal dementia [MIM:600274].

Probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. Stimulates cell-cell adhesion though its association with the E-cadherin/catenin complex. Under conditions of apoptosis or calcium influx, cleaves E-cadherin promoting the disassembly of the E-cadherin/catenin complex and increasing the pool of cytoplasmic beta-catenin, thus negatively regulating Wnt signaling. May also play a role in hematopoiesis.


Homodimer. Component of the gamma-secretase complex, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal complex is sufficient for secretase activity. Other components which are associated with the complex include SLC25A64, SLC5A7, PHB and PSEN1 isoform 3. Predominantly heterodimer of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment. Associates with proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP). Associates with NOTCH1. Component of cadherin/catenin adhesion complexes through direct binding to CDH1 or CDH2. Interaction with CDH1 stabilizes the complex and stimulates cell-cell aggregation. Interaction with CDH2 is essential for trafficking of CDH2 from the endoplasmic reticulum to the plasma membrane. Interacts with CTNND2, CTNNB1, HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL. Interacts through its N-terminus with isoform 3 of GFAP. Interacts with DOCK3 (By similarity).

Defects in PSEN1 are a cause of familial early-onset Alzheimer disease type 3 (AD3) [MIM:607822]. AD3 is the most severe form of the disease, with complete penetrance and an onset occurring as early as 30 years of age. The second form is late- onset AD (LOAD), with mean age of onset greater than 58 years. AD is an autosomal dominant neurodegenerative disorder characterized by progressive dementia, parkinsonism, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major protein found within these deposits is a small, insoluble and highly aggregating polypeptide, beta-amyloid protein (beta- APP42). Defects in PSEN1 result in an overproduction of beta- APP42. Variant Pro-166, a very aggressive mutation that causes onset of AD3 in adolescence, not only induces an exceptionally high increase of beta-APP42 production, but also impairs Notch intracellular domain production and Notch signaling, as well as beta-APP intracellular domain generation.

various regions of the brain, liver, spleen and lymph nodes.

peptidase A22A

PSN2

P49810

 PSEN2

 

 Probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. May function in the cytoplasmic partitioning of proteins.


Interacts with DOCK3 (By similarity). Homodimer. Component of the gamma-secretase complex, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal complex is sufficient for secretase activity, although other components may exist. Interacts with HERPUD1, FLNA, FLNB and PARL.

Defects in PSEN2 are the cause of Alzheimer disease type 4 (AD4) [MIM:606889, 104300]. AD is an autosomal dominant neurodegenerative disorder characterized by progressive dementia, parkinsonism, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. Early onset AD is the most severe form of the disease, with complete penetrance and an onset occurring as early as 30 years of age. The second form is late- onset AD (LOAD), with mean age of onset greater than 58 years.


Three causative genes have been identified that when mutated lead to presenile Alzheimer disease: APP (amyloid precursor protein gene), PSEN1 and PSEN2. These three genes account for half of the families with autosomal dominant presenile AD, which represent approximately 10% of the whole AD population. In addition, apolipoprotein E has been identified as a risk- modifying locus.

Isoform 1 is seen in the placenta, skeletal muscle and heart while isoform 2 is seen in the heart, brain, placenta, liver, skeletal muscle and kidney.

peptidase A22A

RBM25

P49756

 

 

 







Contains 1 PWI domain.

Contains 1 RRM (RNA recognition motif) domain.

REG1A

P05451

 

 

 Might act as an inhibitor of spontaneous calcium carbonate precipitation. May be associated with neuronal sprouting in brain, and with brain and pancreas regeneration.


High expression levels in fetal and infant brains; much lower in adult brains.

Alzheimer disease and Down syndrome patients show enhanced expression of PSP-related transcripts and intraneuronal accumulation of PSP-like proteins in their brains.

In pancreatic acinar cells and, in lower levels, in brain.



Contains 1 C-type lectin domain.

RGPS2

Q86X27

 RALGPS2

 

 Guanine nucleotide exchange factor for the small GTPase RalA. May be involved in cytoskeleton organization. May also be involved in the stimulation of transcription in a Ras-independent fashion (By similarity).

Defects in RALGPS2 gene may be a cause of Alzheimer disease (AD) [MIM:611154].




Contains 1 PH domain.


Contains 1 Ras-GEF domain.

RGS6

P49758

 

 

 Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form. Activity on G(o)-alpha is specifically enhanced by the RGS6/Gbeta5 dimer.







Contains 1 DEP domain.

Contains 1 G protein gamma domain.

Contains 1 RGS domain.

RN146

Q9NTX7

RNF146 

 

 







Contains 1 RING-type zinc finger.

Contains 1 WWE domain.

S12IP

Q8N9Q2

 SFRS12IP1

 

 Possible splicing regulator involved in the control of cellular survival.

Interacts with SFRS12.

Down-regulated in the brains of Alzheimer disease patients.




Contains 1 CCHC-type zinc finger.

SET

Q01105

 

 A chromosomal aberration involving SET is found in some cases of acute undifferentiated leukemia (AUL). Translocation t(6;9)(q21;q34.1) with NUP214/CAN.

 Multitasking protein, involved in apoptosis, transcription, nucleosome assembly and histone binding. Isoform 2 anti-apoptotic activity is mediated by inhibition of the GZMA- activated DNase, NME1. In the course of cytotoxic T-lymphocyte (CTL)-induced apoptosis, GZMA cleaves SET, disrupting its binding to NME1 and releasing NME1 inhibition. Isoform 1 and isoform 2 are potent inhibitors of protein phosphatase 2A. Isoform 1 and isoform 2 inhibit EP300/CREBBP and PCAF-mediated acetylation of histones (HAT) and nucleosomes, most probably by masking the accessibility of lysines of histones to the acetylases. The predominant target for inhibition is histone H4. HAT inhibition leads to silencing of HAT-dependent transcription and prevents active demethylation of DNA. Both isoforms stimulate DNA replication of the adenovirus genome complexed with viral core proteins; however, isoform 2 specific activity is higher.




Widely expressed. Low levels in quiescent cells during serum starvation, contact inhibition or differentiation. Highly expressed in Wilms' tumor.

nucleosome assembly protein (NAP)

SFR12

Q8WXA9

SFRS12

 

 Participates in the regulation of alternative splicing by modulating the activity of other splice facors. Inhibits the splicing activity of SFRS1, SFRS2 and SFRS6. Augments the splicing activity of SFRS3 (By similarity).

Homodimer. Binds SFRS1, SFRS2, SFRS3 and SFRS6. Interacts with the spliceosome (By similarity). Interacts with P18SRP.







splicing factor SR

Contains 1 RRM (RNA recognition motif) domain.

SQSTM

Q13501

 SQSTM1

 Defects in SQSTM1 are a cause of sporadic and familial Paget disease of bone (PDB) [MIM:602080]. PDB is a metabolic bone disease affecting the axial skeleton and characterized by focal areas of increased and disorganized bone turn-over due to activated osteoclasts. Manifestations of the disease include bone pain, deformity, pathological fractures, deafness, neurological complications and increased risk of osteosarcoma. PDB is a chronic disease affecting 2 to 3% of the population above the age of 40 years.

 Adapter protein which binds ubiquitin and may regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. May regulate signaling cascades through ubiquitination. May be involved in cell differentiation, apoptosis, immune response and regulation of K(+) channels.




Ubiquitously expressed.

Contains 1 OPR domain.

Contains 1 UBA domain.

Contains 1 ZZ-type zinc finger.

STH

Q81WL8

 

 The Arg-7 polymorphism may be associated with progressive supranuclear palsy.

 Interacts with PRDX6.




Highest expression in placenta, muscle, fetal brain, and adult brain, with lower expression in heart, kidney, stomach, testis, and adrenal gland. In the central nervous system, highest expression is in temporal lobe, hypothalamus, medulla and spinal cord, with lower expression in other brain regions.




STMN2

Q93045

 

 

 May play a role in neuronal differentiation, and in modulating membrane interaction with the cytoskeleton during neurite outgrowth.




Neuron specific.

stathmin

SYNPO

Q8N3V7

 

 

 Actin-associated protein that may play a role in modulating actin-based shape and motility of dendritic spines and renal podocyte foot processes. Seems to be essential for the formation of spine apparatuses in spines of telencephalic neurons, which is involved in synaptic plasticity (By similarity).




Expressed in cerebral cortex.

synaptopodin

SYUA

P37840

 SNCA

 Defects in SNCA are a cause of autosomal dominant Parkinson disease 1 (PARK1) [MIM:168601, 168600]. Parkinson disease (PD) is a complex, multifactorial disorder that typically manifests after the age of 50 years, although early-onset cases (before 50 years) are known. PD generally arises as a sporadic condition but is occasionally inherited as a simple mendelian trait. Although sporadic and familial PD are very similar, inherited forms of the disease usually begin at earlier ages and are associated with atypical clinical features. PD is characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain.

Defects in SNCA are the cause of Parkinson disease 4 (PARK4) [MIM:605543, 168600].

Defects in SNCA are the cause of Lewy body dementia (DLB) [MIM:127750]. DLB is a neurodegenerative disorder clinically characterized by dementia and parkinsonism, often with fluctuating cognitive function, visual hallucinations, falls, syncopal episodes, and sensitivity to neuroleptic medication. Presence of Lewy bodies are the only essential pathologic features.

Brain iron accumulation type 1 (NBIA1, also called Hallervorden-Spatz syndrome), a rare neuroaxonal dystrophy, is histologically characterized by axonal spheroids, iron deposition, Lewy body (LB)-like intraneuronal inclusions, glial inclusions and neurofibrillary tangles. SNCA is found in LB-like inclusions, glial inclusions and spheroids.

 May be involved in the regulation of dopamine release and transport. Soluble protein, normally localized primarily at the presynaptic region of axons, which can form filamentous aggregates that are the major non amyloid component of intracellular inclusions in several neurodegenerative diseases (synucleinopathies). Induces fibrillization of microtubule- associated protein tau. Reduces neuronal responsiveness to various apoptotic stimuli, leading to a decreased caspase 3 activation.

Deposition of fibrillar amyloid proteins intraneuronally as neurofibrillary tangles is characteristic of Alzheimer disease (AD). SNCA is a minor protein found within these deposits, but a major non amyloid component.

Expressed principally in brain but is also expressed in low concentrations in all tissues examined except in liver. Concentrated in presynaptic nerve terminals.

synuclein

SYUB

Q16143

SNCB

 Brain iron accumulation type 1 (NBIA1, also called Hallervorden-Spatz syndrome), a rare neuroaxonal dystrophy, is histologically characterized by axonal spheroids, iron deposition, Lewy body (LB)-like intraneuronal inclusions, glial inclusions and neurofibrillary tangles. SNCB is found in spheroids but not in inclusions.

 Non-amyloid component of senile plaques found in Alzheimer disease. Could act as a regulator of SNCA aggregation process. Protects neurons from staurosporine and 6 hydroxy dopamine (6OHDA)-stimulated caspase activation in a p53-dependent manner. Contributes to restore the SNCA anti-apoptotic function abolished by 6OHDA. Not found in the Lewy bodies associated with Parkinson disease.




Expressed predominantly in brain; concentrated in presynaptic nerve terminals.

synuclein