Identified in genome-wide association studies (GWAS), the human gene PICALM has been proposed as a susceptibility locus for Alzheimer disease; this is supported by experiments using zebrafish and Drosophila models. PICALM is involved in cellular trafficking, regulation of endocytosis, and clathrin-mediated vesicle formation. There is a single orthologous gene in flies, lap, for which loss-of-function alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\lap is also orthologous to a second human gene, SNAP91. Somatic mutations of PICALM and translocations involving the gene have been associated with acute myeloid leukemia.
A UAS construct of a wild-type human Hsap\PICALM gene has been introduced into flies, but has not been characterized.
Loss-of-function mutations of Dmel\lap are lethal in the third instar larval stage; the larvae are uncoordinated and sluggish, and exhibit neurophysiology and neuroanatomy defects. Reduction in levels of lap effected via RNAi results in an increase a gene marker for autophagy. Dmel\lap was tested for effects upon a transgenically introduced human tau gene (Hsap\MAPT); in this system, reduction in lap effected via RNAi results in increased levels of tau protein. Physical and genetic interactions have been described for Dmel\lap; see below and in the gene report for lap.
[updated Sep. 2018 by FlyBase; FBrf0222196]
Alzheimer disease (AD) is the most common form of progressive dementia in the elderly. [from MIM:104300; 2016.01.08]
Memory loss is the most common sign of Alzheimer disease. As the disorder progresses, some people with AD experience personality and behavioral changes; other common symptoms include agitation, restlessness, withdrawal, and loss of language skills. Total care is usually required during the advanced stages of the disease. Affected individuals usually survive 8 to 10 years after the appearance of symptoms, but the course of the disease can range from 1 to 25 years. Death usually results from pneumonia, malnutrition, or general body wasting. [from Genetics Home Reference, Alzheimer disease; 2016.01.08]
Alzheimer disease can be classified as early-onset or late-onset. The signs and symptoms of the early-onset form appear before age 65, while the late-onset form appears after age 65. The early-onset form is much less common than the late-onset form, accounting for less than 5 percent of all cases of Alzheimer disease. [from Genetics Home Reference, Alzheimer disease; 2016.01.08]
Several genome-wide association studies (GWAS) and subsequent supporting studies have implicated PICALM in the development of Alzheimer disease.
PICALM is associated with Alzheimer disease in multiple GWAS studies (see GWAS Catalog, below in 'External links').
A large genome-wide association meta-analysis of clinically diagnosed late-onset Alzheimer's disease (94,437 individuals) supports previous studies implicating PICALM as a susceptibility locus for AD (Kunkle et al., 2019; pubmed:30820047).
PICALM encodes a clathrin assembly protein, which recruits clathrin and adaptor protein complex 2 (AP2) to cell membranes at sites of coated-pit formation and clathrin-vesicle assembly; it is involved in AP2-dependent clathrin-mediated endocytosis at the neuromuscular junction. [from Gene Cards, PICALM; 2017.04.04]
PICALM is involved in cellular trafficking, regulation of endocytosis, and clathrin-mediated vesicle formation; it is associated with iron homeostasis and cell proliferation (summary by Stern et al., 2014; pubmed:24898977). [from MIM:603025; 2017.04.04]
Many to one (2 human to 1 Drosophila); the second human gene is SNAP91.
High-scoring ortholog of human genes PICALM and SNAP91 (1 Drosophila to 2 human). Dmel\lap shares 37-38% identity and 46-51% similarity with the human genes.
