PICALM is an accessory protein in the endocytic pathway. Ubiquitously expressed, PICALM binds to clathrin and its adaptor proteins, which together regulate the formation of the clathrin lattice during endocytosis. PICALM was identified in one of the first large-scale genome-wide association studies (GWAS) for late-onset Alzheimer’s disease and remains one of the top 10 risk genes on AlzGene. Multiple single nucleotide polymorphisms (SNPs) within and around the PICALM gene have been associated with AD; however, the pathogenic variant(s) and the underlying mechanisms by which they affect a person’s risk of AD remain unknown.
PICALM is involved in many cellular processes, with many opportunities to influence AD pathogenesis. A prominent hypothesis holds that it affects internalization of APP and thus the production of Aβ. Additionally, PICALM could act through effects on the endocytosis and trafficking of other molecules important for neuronal function.
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- Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009 Oct;41(10):1088-93. PubMed.
- Jun G, Naj AC, Beecham GW, Wang LS, Buros J, Gallins PJ, Buxbaum JD, Ertekin-Taner N, Fallin MD, Friedland R, Inzelberg R, Kramer P, Rogaeva E, St George-Hyslop P, Cantwell LB, Dombroski BA, Saykin AJ, Reiman EM, Bennett DA, Morris JC, Lunetta KL, Martin ER, Montine TJ, Goate AM, Blacker D, Tsuang DW, Beekly D, Cupples LA, Hakonarson H, Kukull W, Foroud TM, Haines J, Mayeux R, Farrer LA, Pericak-Vance MA, Schellenberg GD. Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol. 2010 Dec;67(12):1473-84. PubMed.
- Bettens K, Sleegers K, Van Broeckhoven C. Genetic insights in Alzheimer's disease. Lancet Neurol. 2013 Jan;12(1):92-104. PubMed.
- Elias-Sonnenschein LS, Bertram L, Visser PJ. Relationship between genetic risk factors and markers for Alzheimer's disease pathology. Biomark Med. 2012 Aug;6(4):477-95. PubMed.
- Xu W, Tan L, Yu JT. The Role of PICALM in Alzheimer's Disease. Mol Neurobiol. 2014 Sep 4; PubMed.