Genome-wide association studies (GWAS) have suggested that variants of the human gene UCHL1 may be associated with development of type 2 diabetes. UCHL1 encodes a deubiquitinas that is primarily expressed in neural tissues, including high levels in the brain; a paralogous gene, UCHL3, is more widely expressed. UCHL1 has also been implicated in form of spastic paraplegia (SPG7; MIM:615491) and as a susceptibility locus for Parkinson disease (PARK5, MIM:613643, FBhh0000859).
A UAS construct of a tagged human Hsap\UCHL1 gene has been introduced into flies, but has not been characterized in the context of this disease model.
There is a single Drosophila gene orthologous to both UCHL1 and UCHL3, Dmel\Uch. Multiple genetic reagents have been generated for Dmel\Uch, including a knock-out mutation, RNAi-targeting constructs, and alleles caused by insertional mutagenesis. Loss of function mutations of Dmel\Uch result in diabetic-like phenotypes: increased levels of hemolymph glucose, triglycerides, glycogen, and trehalose. Nervous system-specific knockdown is sufficient to produced diabetes phenotypes; tissue-specific expression in either the gut or muscle is not. Interactions with genes with roles in insulin signaling have been characterized. It is postulated that UCHL1 regulates insulin signaling by acting as a deubiquitinase of IRS1. See the Human Disease Model report 'diabetes mellitus type 2, susceptibility to, IRS1,2-related' (FBhh0000171).
Diabetic neuropathy manifesting as numbness to external stimuli has been investigated using this disease model. Animals carrying loss-of-function mutations of Uch exhibit delayed response to noxious stimuli and axonal degeneration of sensory neurons of the legs. See the Human Disease Model report 'diabetic neuropathy' (FBhh0001399).
[updated Feb. 2024 by FlyBase; FBrf0222196]
Diabetes mellitus, type 2, also called non-insulin-dependent diabetes mellitus, occurs when cells become resistant to the effects of insulin, thus disrupting the body's ability to metabolize glucose and to properly control the amount of sugar in the blood. [from Genetics Home Reference, Diabetes; 2016.02.02]
Over time, high blood glucose can lead to serious problems such as cataracts and/or retinopathy, impaired kidney function, diabetic neuropathy, and macrovascular complications (heart attack, stroke, peripheral vascular disease). [from endocrineweb; http://www.endocrineweb.com/conditions/type-2-diabetes/type-2-diabetes-complications]
UCHL1 encodes Ubiquitin C-Terminal Hydrolase L1, a deubiquitinase that acts in a number of regulatory capacities.
Many to one: 2 human genes to 1 Drosophila gene.
Many to one: 2 human genes to 1 Drosophila gene.
High-scoring ortholog of human UCHL1 and UCHL3 (1 Drosophila to 2 human).
