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FB2026_01
,
released March 12, 2026
This report describes Parkinson disease 17 (PARK17) which is a subtype of Parkinson disease; PARK17 exhibits autosomal dominant inheritance. The human gene implicated in this disease is VPS35, which encodes a component of the retromer complex; the retromer complex is involved in endosome-trans-Golgi trafficking and the recycling of membrane-associated proteins. There is a single fly ortholog of human VPS35, Dmel\Vps35, for which classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple different UAS constructs of the human Hsap\VPS35 gene have been introduced into flies, including wild-type VPS35 and genes carrying mutational lesions implicated in PARK17. Partial heterologous rescue (functional complementation) of the Dmel\Vps35 phenotype is observed.
Variant(s) implicated in human disease tested (as transgenic human gene, VPS35): the D620N variant form has been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): D628N in the fly Vps35 gene (corresponds to D620N in the human VPS35 gene).
Loss-of-function mutations in the Dmel\Vps35 gene are lethal, usually in the larval stage; defects in larval neuromuscular junctions are observed; larval locomotion is dramatically reduced. Physical interactions of the Dmel\Vps35 protein product have been described; see below and in the Vps35 gene report. Phenotypic assays using the fly gene have allowed characterization of genetic interactions, including with the fly orthologs of genes implicated in other forms of Parkinson disease.
[updated Jan. 2020 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]
[PARKINSON DISEASE 17; PARK17](https://omim.org/entry/614203)
[VPS35 RETROMER COMPLEX COMPONENT; VPS35](https://omim.org/entry/601501)
Parkinson disease 17 is an adult-onset form of the disorder. It is phenotypically similar to idiopathic Parkinson disease [from MIM:614203; 2015.03.04]. See general description of Parkinson disease symptoms and phenotype, above.
PARK17 is inherited as an autosomal dominant with incomplete penetrance; it is caused by mutation in the VPS35 gene [from MIM:614203; 2015.03.04].
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 VPS35 gene encodes a component of the retromer cargo-recognition complex critical for endosome-trans-Golgi trafficking and the recycling of membrane-associated proteins (summary by Vilarino-Guell et al., 2011, PMID: 21763482) [from MIM:601501; 2015.03.04].
One to one: 1 human to 1 Drosophila.
Ortholog of human VPS35 (1 Drosophila to 1 human). Dmel\Vps35 shares 61% identity and 78% similarity with human VPS35.