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Mol Brain. 2014 Oct 8;7:73. doi: 10.1186/s13041-014-0073-y.

In vivo evidence of pathogenicity of VPS35 mutations in the Drosophila.

Author information

1
National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore. mitsuvolvo@gmail.com.
2
National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore. joanne.toh.y.e@singhealth.com.sg.
3
National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore. patrick.ho.g.h@sgh.com.sg.
4
National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore. murnittio@yahoo.co.uk.
5
Department of Clinical Research, Singapore General Hospital, 169856, Singapore, Singapore. murnittio@yahoo.co.uk.
6
National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore. gnrtek@sgh.com.sg.
7
Department of Neurology, Singapore General Hospital, 169856, Singapore, Singapore. gnrtek@sgh.com.sg.
8
Duke-NUS Graduate Medical School, 8 College Road, 169857, Singapore, Singapore. gnrtek@sgh.com.sg.

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.

PMID:
25288323
PMCID:
PMC4193144
DOI:
10.1186/s13041-014-0073-y
[Indexed for MEDLINE]
Free PMC Article

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