Multiple GWAS studies have implicated the human gene TOMM40 in the development of late-onset Alzheimer disease. TOMM40, which encodes the channel subunit of the mitochondrial outer membrane (TOM) complex, is a core component of the mitochondrial protein-importing system. The most closely related gene in Drosophila is Tom40, for which RNAi targeting constructs and an allele caused by insertional mutagenesis have been generated. Two paralogous genes in Drosophila, tomboy40 and CG4520, are expressed predominantly in testis.
The human TOMM40 gene has not been introduced into flies.
Animals homozygous for a severe loss-of-function mutation of Dmel\Tom40 die in the embryonic stage. Assessed in the larval fat body cells, reduced levels of Tom40 effected by RNAi result in accumulation of ubiquitin-positive protein aggregates engulfed by autophagosome-like membranes. The protein aggregates contain mitochondrial preproteins, cytosolic proteins, and proteasome subunits. Autophagy is induced, but the majority of autophagosomes fail to fuse with lysosomes. Reduced levels of Tom40 in the nervous system also results in protein aggregate formation and subsequent degeneration of neurons. A small number of physical and genetic interactions for Dmel\Tom40 have been described; see below and in the Tom40 gene report.
[updated Feb. 2020 by FlyBase; FBrf0222196]
Alzheimer disease (AD) is the most common form of progressive dementia in the elderly. [from OMIM: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]
Multiple GWAS studies have implicated TOMM40 in the development of late-onset Alzheimer disease (see GWAS Catalog, below in 'External links').
TOMM40 encodes a protein that is localized in the outer membrane of the mitochondria. It is the channel-forming subunit of the translocase of the mitochondrial outer membrane (TOM) complex that is essential for import of protein precursors into mitochondria. [Gene Cards, TOMM40; 2020.02.11]
Many to many: 2 human to 3 Drosophila.
High-scoring ortholog of human TOMM40; moderate-scoring ortholog of human TOMM40L. Dmel\Tom40 shares 41-52% identity and 59-65% similarity with the human genes. Additional related genes in flies are tomboy40 and CG4520; expression of both of these genes is testis-enriched, with little or no neural expression.