The human gene SH3GL2 has been identified as a possible susceptibility locus for Parkinson disease. SH3GL2 encodes a protein implicated in synaptic vesicle endocytosis. There is one high-scoring fly ortholog, Dmel\EndoA, for which amorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
UAS constructs of the human gene Hsap\SH3GL2 have been introduced into flies, including wild-type SH3GL2 and a variant implicated in disease (G276V). See the 'Disease-Implicated Variants' table below.
Flies homozygous for a null mutation in Dmel\EndoA exhibit severe defects in synaptic vesicle endocytosis. When pan-neuronally expressed in Drosophila larvae mutant for Dmel\EndoA, both wild-type and mutant Hsap\SH3GL2 localize to fly synapses, and larvae expressing either demonstrate endocytosis of synaptic vesicles that is not significantly different from that observed in wild-type flies. However, when stimulated with a Ca[[2+]], only wild-type Hsap\SH3GL2 upregulates synaptic autophagy and redistributes from the periphery to a more luminal localization (FBrf0256464).
[updated Apr. 2024 by FlyBase; FBrf0222196]
Parkinson disease (PD) is a neurodegenerative disease usually typified by slow onset in mid to late adulthood; there are also early-onset and juvenile forms of the disease. Symptoms worsen over time and include resting tremor, muscular rigidity, bradykinesia [abnormal slowness of movement], and postural instability [impaired balance and coordination]; additional symptoms may include postural abnormalities, dysautonomia [symptoms caused by malfunction of the autonomic nervous system], dystonic cramps, and dementia. Parkinson disease is the second-most common neurodegenerative disease (after Alzheimer disease), affecting approximately 1% of the population over 50 (Polymeropoulos et al., 1996, pubmed:8895469). [from MIM:168600; 2013.07.23]
Parkinson disease is described as early-onset disease if signs and symptoms begin before age 50. Early-onset cases that begin before age 20 may be referred to as juvenile-onset disease. [from Genetics Home Reference, GHR_condition:parkinson-disease, 2015.02.13]
A missense mutation in SH3GL2 has been implicated in Parkinson disease risk (Bademosi, et al., 2023, pubmed:36827984; FBrf0256464).
SH3GL2 is implicated in synaptic vesicle endocytosis. May recruit other proteins to membranes with high curvature. Required for BDNF-dependent dendrite outgrowth. Cooperates with SH3GL2 to mediate BDNF-NTRK2 early endocytic trafficking and signaling from early endosomes [UniProtKB/Swiss-Prot: Q99962].
Enables identical protein binding activity. Involved in negative regulation of blood-brain barrier permeability; negative regulation of gene expression; and negative regulation of protein phosphorylation. Located in perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]
Many to one (3 human to 1 Drosophila); SH3GL2 has one high-scoring Drosophila ortholog, EndoA.
High-scoring ortholog of human SH3GL1, SH3GL2, SH3GL3 (1 Drosophila to 3 human).
