The human auxilin genes DNAJC6 (DnaJ heat shock protein C6) and GAK (cyclin G associated kinase) have been implicated as causative or susceptibility loci for Parkinson disease. The genes encode proteins that function in the pathway of clathrin-mediated endocytosis; DNAJC6 is expressed specifically in neurons, GAK appears to be ubiquitously expressed. In Drosophila, there is a single gene, aux, orthologous to both human genes. Classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\aux. See also 'Parkinson disease 19A/B' (FBhh0000594; MIM:615528).
UAS constructs of both human genes, wild-type Hsap\DNAJC6 and wild-type Hsap\GAK, have been introduced into flies, but have not been characterized.
Animals homozygous for amorphic alleles of Dmel\aux die in the late embryonic stage. Loss-of-function effected by RNAi against aux driven in dopaminergic neurons results in progressive decline of adult locomotor abilities (climbing assay), shorter adult lifespan, and age-dependent loss of dopaminergic neurons in the brain.
[updated Sep. 2018 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]
GAK is associated with Parkinson disease in multiple GWAS studies (see GWAS Catalog, below in 'External links').
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, FBhh0000232) have been shown to interact with genes involved in endocytic membrane trafficking.
The DNAJC6 gene encodes a neuronal protein that functions specifically in the pathway of clathrin-mediated endocytosis. It shares homology with the ubiquitously expressed GAK. Both proteins act as co-chaperones to support the HSC70-dependent clathrin uncoating of clathrin-coated vesicles (summary by Yim et al., 2010; pubmed:20160091). [from MIM:608375; 2017.08.11]
Many to one: 2 human to 1 Drosophila; the human genes are GAK and DNAJC6.
Many to one: 2 human to 1 Drosophila; the human genes are GAK and DNAJC6.
High-scoring ortholog of human gene GAK; moderate-scoring ortholog of human DNAJC6 (1 Drosophila to 2 human). Dmel\aux shares 36% identity and 50% similarity with GAK; it shares 31% identity and 44% similarity with DNAJC6.
