title: In vivo evidence of pathogenicity of VPS35 mutations in the Drosophila.
abstract: Mutations of VPS35, a component of the retromer complex have been associated with late onset familial Parkinson's disease. The D620N mutation in VPS35 appears to be most prevalent, however, P316S was found in two cases within the same family and a control, whereas L774M was identified in 6 cases and 1 control. In vivo evidence of their pathogenicity is lacking. Here we investigated the in vivo effects of P316S, D620N and L774M using Drosophila as a model. We generated transgenic human VPS35-expressing mutations and demonstrated that VPS35 D620N transgenic flies led to late-onset loss of TH-positive DA neurons, poor mobility, shortened lifespans and increased sensitivity to rotenone, a PD-linked environmental toxin, with some of these phenotypes observed for P316S but not in L774M transgenic flies. We conclude that D620N and to a smaller extent P316S are associated with pathogenicity in PD.
authors.affiliation: National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore. mitsuvolvo@gmail.com.
authors.forename: Hua-shan
authors.initials: HS
authors.lastname: Wang
authors.affiliation: National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore. joanne.toh.y.e@singhealth.com.sg.
authors.forename: Joanne
authors.initials: J
authors.lastname: Toh
authors.affiliation: National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore. patrick.ho.g.h@sgh.com.sg.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ho
authors.affiliation: National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore. murnittio@yahoo.co.uk.
authors.forename: Murni
authors.initials: M
authors.lastname: Tio
authors.affiliation: Department of Clinical Research, Singapore General Hospital, 169856, Singapore, Singapore. murnittio@yahoo.co.uk.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore. gnrtek@sgh.com.sg.|Department of Neurology, Singapore General Hospital, 169856, Singapore, Singapore. gnrtek@sgh.com.sg.|Duke-NUS Graduate Medical School, 8 College Road, 169857, Singapore, Singapore. gnrtek@sgh.com.sg.
authors.forename: Eng-King
authors.initials: EK
authors.lastname: Tan
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation / Q000235:genetics*; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012402:Rotenone / Q000494:pharmacology; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D029721:Drosophila Proteins; D033921:Vesicular Transport Proteins; C527271:Vps35 protein, Drosophila; D012402:Rotenone