The human gene AP2M1 has been identified as a possible susceptibility locus for Parkinson disease. AP2M1 encodes a subunit of the assembly protein complex 2 (AP2) which is involved in clathrin-dependent endocytosis. There is a single ortholgous gene in Drosophila, AP-2μ, but the Drosophila gene has not been used in this disease model.
UAS constructs of the human Hsap\AP2M1 have been introduced into flies, including wild-type and a variant (T156A) lacking a critical phosphorylation site. Using a GAL4 driver specific to dopaminergic and serotonin neurons, overexpression of either wild-type AP2M1 or the T156A variant induces neurodegeneration in the major dopaminergic clusters and total dopaminergic neurons.
Based on the hypothesis that LRRK2-dependent phosphorylation of AP2M1 has a role in Parkinson dopaminergic neurodegeneration, the impact of the Hsap\AP2M1 transgenes on the LRRK2 disease model in flies (Parkinson disease 8, FBhh0000011) has been investigated. In the same assay using a driver specific to dopaminergic and serotonin neurons, overexpression of the human Hsap\LRRK2 gene also results in neurodegeneration in the major dopaminergic clusters and total dopaminergic neurons. Overexpression of both LRRK2 and wild-type AP2M1 results in significantly more extreme phenotypes than either one alone. Results of overexpression of LRRK2 and of the T156A AP2M1 variant are variable and less extreme.
[updated Aug. 2021 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]
AP2M1 has been implicated in Parkinson disease risk (Bandres-Ciga, et al., 2019; pubmed:30675927).
AP2M1 encodes a subunit of the heterotetrameric coat assembly protein complex 2 (AP2), which belongs to the adaptor complexes medium subunits family. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles), which are destined for fusion with the early endosome The AP2M1 protein is required for the activity of a vacuolar ATPase, which is responsible for proton pumping occurring in the acidification of endosomes and lysosomes. [Gene Cards, AP2M1; 2021.08.12]
The endocytic membrane-trafficking pathway and disruption of synaptic vesicle endocytosis appear to play major roles in the risk of Parkinson disease. A substantial amount of genetic variation in PD and parkinsonism has been associated with vesicle trafficking via endosomal gene alterations. (Bandres-Ciga et al., 2019, pubmed:30675927; Nguyen et al., 2019, pubmed:30509690). Relevant genes include DNAJC6 (see FBhh0000594, FBhh0000593), SYNJ1 (see FBhh0000626), GAK (see FBhh0000593) and SH3GL2, which are linked to clathrin-coated vesicles, and VPS35 (see FBhh0000030) and DNAJC13 (see FBhh0001155), which participate in recycling components from the endosomes to the Golgi. In addition, LRRK2 (see FBhh0000011) and PLA2G6 (see FBhh0000243) have been shown to interact with genes involved in endocytic membrane trafficking.
One to one: 1 human gene to 1 Drosophila gene.
