Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Oct 8:7:73.
doi: 10.1186/s13041-014-0073-y.

In vivo evidence of pathogenicity of VPS35 mutations in the Drosophila

Hua-shan Wang  1 , Joanne Toh  2 , Patrick Ho  3 , Murni Tio  4 , Yi Zhao  5 , Eng-King Tan  6   7   8
Affiliations

In vivo evidence of pathogenicity of VPS35 mutations in the Drosophila

Hua-shan Wang et al. Mol Brain. .

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Expression of VPS35 pathogenic variant D620N in flies result in DA neuronal degeneration and locomotive dysfunction. (A, B) Bar graphs show number of TH-positive DA neurons in flies at 20 and 60 days after eclosion (n = 3, cohort of 10). (C) Representative confocal images of whole mount brains 60 days after eclosion of VPS35 wild type, P316S and D620N flies with magnified views of PPL1 cluster (boxed on the right). (D) Bar graph shows age-dependent climbing scores of female flies at different days after eclosion. Percentage of flies that reached the top of the column after 1 min were counted (n = 3, cohort of 20). (E) Survival curves were plotted as percentage of living flies. (n = 3, cohort of 100).
Figure 2
Figure 2
Exposure of VPS35 P316S and D620N mutant flies to rotenone accelerates DA neuronal loss. (A) Bar graph shows the quantification of the number of DA neurons in different clusters of various fly species 15 days after rotenone treatment (n = 3, cohort of 10). (B) Representative confocal images showing TH-positive DA neurons in the PPL1 cluster of rotenone treated fly species in VPS35 wild type, P316S and D620N flies.
See this image and copyright information in PMC

References

    1. Tan EK, Skipper LM. Pathogenic mutations in Parkinson disease. Hum Mutat. 2007;28(7):641–653. doi: 10.1002/humu.20507. - DOI - PubMed
    1. Skinner C, Seaman M, Skinner C, Seaman M. The role of retromer in neurodegenerative disease. In: St. George-Hyslop PH, Mobley WCC, Yves C, editors. Research and Perspectives in Alzheimer’s Disease. Heidelberg: Springer Berlin; 2009. pp. 125–140.
    1. Bonifacino JS, Hurley JH. Retromer. Curr Opin Cell Biol. 2008;20(4):427–436. doi: 10.1016/j.ceb.2008.03.009. - DOI - PMC - PubMed
    1. Zimprich A, Benet-Pagès A, Struhal W, Graf E, Eck SH, Offman MN, Haubenberger D, Spielberger S, Schulte EC, Lichtner P, Rossle SC, Klopp N, Wolf E, Seppi K, Pirker W, Presslauer S, Mollenhauer B, Katzenschlager R, Foki T, Hotzy C, Reinthaler E, Harutyunyan A, Kralovics R, Peters A, Zimprich F, Brücke T, Poewe W, Auff E, Trenkwalder C, Rost B, et al. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am J Hum Genet. 2011;89(1):168–175. doi: 10.1016/j.ajhg.2011.06.008. - DOI - PMC - PubMed
    1. Vilariño-Güell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, Lincoln SJ, Soto-Ortolaza AI, Cobb SA, Wilhoite GJ, Bacon JA, Behrouz B, Melrose HL, Hentati E, Puschmann A, Evans DM, Conibear E, Wasserman WW, Aasly JO, Burkhard PR, Djaldetti R, Ghika J, Hentati F, Krygowska-Wajs A, Lynch T, Melamed E, Rajput A, Rajput AH, Solida A, Wu RM, Uitti RJ, et al. VPS35 mutations in Parkinson disease. Am J Hum Genet. 2011;89(1):162–167. doi: 10.1016/j.ajhg.2011.06.001. - DOI - PMC - PubMed

Publication types

LinkOut - more resources