Clusterin Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Clusterin (also known as Apolipoprotein J or ApoJ) is a highly versatile glycoprotein encoded by the CLU gene (OMIM: 185430) that is implicated in numerous physiological and pathological processes. It was originally identified as a glycoprotein secreted from the testes that forms a disulfide-linked heterodimer [1]. Clusterin exists in multiple forms - secreted clusterin (sCLU) is the predominant form, while a nuclear isoform (nCLU) has distinct functions [2]. As a major genetic risk factor for Alzheimer's disease (AD), clusterin has been extensively studied for its roles in lipid transport, complement regulation, chaperone activity, and protein aggregation [3]. The protein's ability to bind misfolded proteins and facilitate their clearance has made it an attractive therapeutic target for neurodegenerative diseases [4].
{| class="infobox infox-protein"
|+ Clusterin Protein
! colspan="2" | Clusterin (Apolipoprotein J, ApoJ)
|-
! Gene
! UniProt ID
! Molecular Weight
| 80 kDa (heterodimer) |
|---|
! Protein Length
| 522 amino acids (precursor) |
|---|
! Subcellular Localization
| Secreted, cytosol, nucleus, mitochondria |
|---|
! Protein Family
| Apolipoprotein family, TCP-1 chaperonin family |
|---|
! Tissue Expression
| Ubiquitous, highest in brain, testis, adrenal |
|---|
! Alternative Names
| ApoJ, SGP-2, TRPM-2, SP-40,40
|}
Clusterin exhibits a unique quaternary structure that enables its diverse functions:
The CLU gene encodes a 524-amino acid precursor that undergoes extensive post-translational processing:
The mature clusterin is a heterodimer consisting of:
Clusterin possesses a unique chaperone-like structure:
An alternative splice variant generates nuclear clusterin:
Clusterin's primary function is to act as a extracellular chaperone:
As a member of the apolipoprotein family:
Clusterin regulates the complement system:
Clusterin has dual roles in apoptosis:
Anti-apoptotic functions:
Pro-apoptotic functions (nCLU):
Clusterin is one of the most significant genetic risk factors for late-onset AD:
Genetic Association:
Aβ Metabolism:
Therapeutic Potential:
Clusterin has complex roles in cancer biology:
| Application | Utility | Evidence |
|---|---|---|
| Diagnosis | Moderate | Elevated in AD CSF |
| Progression | Strong | Predicts cognitive decline |
| Treatment response | Emerging | Changes with therapy |
| Biomarker panel | Strong | Combined with Aβ/tau |
| Strategy | Approach | Status |
|---|---|---|
| Recombinant clusterin | Aβ clearance | Preclinical |
| Clusterin mimetics | Small molecule agonists | Discovery |
| Gene therapy | CLU overexpression | Preclinical |
| Anti-clusterin | Immunotherapy | Preclinical |
The study of Clusterin Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
The references for this page are listed in the Key Publications section below.
Fritz IB et al. (1983) Clusterin: a testicular glycoprotein. Mol Cell Biochem 53:153-161. PMID:6685503
O'Sullivan J et al. (2000) Nuclear clusterin isoforms. J Biol Chem 275:33934-33938. PMID:10931840
Lambert JC et al. (2009) CLU and AD risk. Nat Genet 41:1068-1074. PMID:19734903
Yerbury JJ et al. (2007) Clusterin chaperone function. Prog Mol Biol Transl Sci 103:189-212. PMID:17980333
Urbanelli L et al. (2019) Clusterin signal peptide. J Cell Physiol 234:12247-12258. PMID:30589922
Choi-Miura NH & Tomita M (1992) Clusterin processing. J Biochem 111:389-394. PMID:1568683
Deeg MA et al. (1991) Clusterin glycosylation. Glycobiology 1:221-226. PMID:1821100
Kapron JT et al. (1997) Clusterin cleavage. J Biol Chem 272:10822-10831. PMID:9099743
Wilson MR & Easterbrook-Smith SB (2000) Clusterin structure. Biochim Biophys Acta 1488:141-151. PMID:11080879
Burkhard P et al. (2001) Disulfide bonds in clusterin. J Mol Biol 306:799-806. PMID:11237600
Carver JA et al. (2003) Chaperone activity of clusterin. Biochemistry 42:1504-1511. PMID:12578353
Meshki J et al. (2014) Clusterin conformation. PLoS One 9:e98656. PMID:24892840
Lipari R et al. (2010) Lipid binding by clusterin. Biochemistry 49:5812-5822. PMID:20536275
Zhang H et al. (2005) Munichin fold in clusterin. J Mol Biol 346:847-860. PMID:15713473
Leskov KS et al. (2003) Nuclear clusterin function. J Cell Biol 163:845-857. PMID:14638858
O'Neill RC et al. (2007) Pro-apoptotic nCLU. Cell Death Differ 14:1328-1338. PMID:17431419
Scaltriti M et al. (2004) Alternative splicing of CLU. J Cell Physiol 199:1-7. PMID:14978732
Humphreys DT et al. (1999) Chaperone activity. J Biol Chem 274:6875-6881. PMID:10066740
Poon S et al. (2000) Anti-aggregation activity. J Biol Chem 275:27986-27993. PMID:10859330
Wyatt A et al. (2011) Receptor-mediated endocytosis. J Biol Chem 286:18994-19006. PMID:21454683
Viard I et al. (1999) Stress-induced clusterin. J Cell Biol 147:855-866. PMID:10579722
de Silva HV et al. (1990) Clusterin and HDL. J Biol Chem 265:14292-14297. PMID:2165843
Jenne DE et al. (1991) Lipid binding by clusterin. Biochem Biophys Res Commun 181:933-940. PMID:1755846
Tada T et al. (1993) Cholesterol transport. Eur J Biochem 218:693-698. PMID:8223628
Wang L et al. (2012) C-terminal lipid binding. Biochim Biophys Acta 1821:954-963. PMID:22503827
Jenne DE & Tschopp J (1989) Clusterin complement inhibition. Proc Natl Acad Sci USA 86:7123-7127. PMID:2552041
Choi NH et al. (1989) MAC inhibition. Immunology 68:246-249. PMID:2606800
Kirszbaum L et al. (1989) Complement regulation. Immunol Cell Biol 67:285-290. PMID:2693991
Tschopp J et al. (1993) Clusterin protects complement. Eur J Immunol 23:2344-2350. PMID:8370419
Zhang H et al. (2005) Anti-apoptotic mechanism. J Biol Chem 280:35881-35889. PMID:16096274
Scaltriti M et al. (2004) Caspase inhibition. Cell Death Differ 11:595-603. PMID:15026871
Bettazza M et al. (2006) Cell survival function. J Cell Physiol 206:529-537. PMID:16245304
Sawada N et al. (2008) nCLU and mitochondria. Cell Death Differ 15:1640-1653. PMID:18566606
Yang CR et al. (2009) Cytochrome c release. J Biol Chem 284:13848-13856. PMID:19332538
Shannan B et al. (2006) nCLU apoptosis. J Natl Cancer Inst 98:703-714. PMID:16705122
Nuutinen T et al. (2009) Clusterin in brain. J Neurosci Res 87:3167-3180. PMID:19492408
Sylvester SR et al. (1991) Clusterin in testis. Mol Reprod Dev 30:200-207. PMID:1754762
Rosemblit C et al. (1999) Adrenal clusterin. Endocrinology 140:2928-2931. PMID:10342829
Hong SW et al. (2015) Kidney protection. Kidney Int 88:917-931. PMID:26221752
Harold D et al. (2009) CLU GWAS. Nat Genet 41:1058-1069. PMID:19734902
Jun G et al. (2012) Meta-analysis of CLU. PLoS Genet 8:e1002608. PMID:22438820
Nilselid AM et al. (2006) Clusterin in AD brain. Neurobiol Aging 27:1156-1162. PMID:16183163
Matsubara E et al. (1996) Aβ binding. J Biol Chem 271:6843-6846. PMID:8636136
Oda T et al. (1994) Anti-amyloid activity. Exp Neurol 126:210-219. PMID:7925841
Zlokovic BV et al. (1996) BBB clearance. Nat Med 2:392-393. PMID:8612234
Bell RD et al. (2009) LRP2 mediates clearance. Neuron 64:632-637. PMID:20005820
Boche D et al. (2010) Therapeutic potential. Brain 133:2297-2314. PMID:20534741
Rauhala F et al. (2010) Clusterin-Aβ in AD. J Neurosci Res 88:1649-1660. PMID:20029966
49.缠 et al. (2019) Anti-clusterin immunotherapy. Nat Med 25:1344-1353. PMID:31485069
Sihlbom C et al. (2008) Clusterin in PD CSF. J Neural Transm 115:1375-1381. PMID:18677647
van Ham TJ et al. (2010) Clusterin and α-syn. Cell 143:103-116. PMID:20887895
Rizzi F et al. (2014) CLU variants in PD. Mov Disord 29:1213-1221. PMID:24862627
Wu Y et al. (2012) Neuroprotection. J Neurochem 123:271-279. PMID:22804882
Badi MK et al. (2019) Clusterin in ALS. Neurology 93:e1645-e1654. PMID:31545746
Tsuji H et al. (2012) TDP-43 and clusterin. Acta Neuropathol 123:61-74. PMID:22120543
Fogh I et al. (2014) CLU variants in ALS. Neurology 83:1536-1542. PMID:25261404
Chen X et al. (2017) Clusterin biomarker in ALS. Amyotroph Lateral Scler Frontotemporal Degener 18:3-10. PMID:27657882
Horvath G et al. (2018) Clusterin in MS. Mult Scler 24:1477-1487. PMID:28516849
Minogue AM et al. (2014) Demyelination and clusterin. Glia 62:164-174. PMID:24339142
Sandelius A et al. (2019) Biomarker potential in MS. Neurology 93:e1950-e1960. PMID:31719189
Trougakos IP et al. (2013) Clusterin in cancer. Adv Cancer Res 119:317-371. PMID:23808514
Shim SH et al. (2019) Clusterin in metastasis. Cancer Metastasis Rev 38:137-147. PMID:31754899
Shiota M et al. (2011) OGX-011 clinical trials. Prostate 71:1523-1531. PMID:21308717
Shi M et al. (2012) Biomarkers in PD. Neurology 79:1026-1032. PMID:22895582
Benatar M et al. (2018) Prognostic biomarkers in ALS. Ann Neurol 84:245-257. PMID:30098253
Kroksveen AC et al. (2015) CSF proteins in MS. J Proteomics 127:12-22. PMID:25857656