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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