Open Access

High expression levels of the D686N Parkinson's disease mutation in VPS35 induces α-synuclein-dependent toxicity in yeast

  • Authors:
    • Yi Huang
    • Xiang Chen
    • Xiaofei He
    • Caifeng Guo
    • Xicui Sun
    • Fengyin Liang
    • Simei Long
    • Xilin Lu
    • Luyang Feng
    • Wenyuan Guo
    • Yixuan Zeng
    • Zhong Pei
  • View Affiliations

  • Published online on: May 9, 2017     https://doi.org/10.3892/mmr.2017.6551
  • Pages: 254-262
  • Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder that affects ~2% of the human population aged >65. α‑synuclein serves a role in the pathogenesis of PD as it is a primary component of Lewy bodies, a pathological feature of PD. Endosomal‑lysosomal dysfunction may be a key factor involved in the pathophysiology of PD, and may cause PD‑associated neurodegeneration via α‑synuclein‑dependent and ‑independent mechanisms. The D620N mutation in the endosomal‑lysosomal gene, vacuolar protein sorting‑associated protein 35 (VPS35), has been linked to PD. To clarify the underlying cellular mechanism of the VPS35 D620N mutation in PD, cell growth and endosomal‑lysosomal functions were investigated in Saccharomyces cerevisiae (sc) yeast cells that exhibited various expression levels of scVPS35, in the presence or absence of non‑toxic expression levels of α‑synuclein. Overexpression of the scVPS35 D686N mutation (the yeast equivalent of D620N) did not lead to toxicity in yeast. However, the co‑expression of high copy numbers of scVPS35 D686N and low copy numbers of α‑synuclein caused toxicity, whereas the co‑expression of scVPS35 wild‑type and α‑synuclein did not. In addition, the scVPS35 D686N mutant enhanced α‑synuclein aggregation. Fragmentation of vacuoles and subsequent inhibition of lysosome function was evident in yeast cells bearing the scVPS35 mutant. The results of the present study suggested that α‑synuclein and scVPS35 were interlinked via the endosomal‑lysosome pathway, which is important for the pathogenesis of PD.
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July-2017
Volume 16 Issue 1

Print ISSN: 1791-2997
Online ISSN:1791-3004

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Copy and paste a formatted citation
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Spandidos Publications style
Huang Y, Chen X, He X, Guo C, Sun X, Liang F, Long S, Lu X, Feng L, Guo W, Guo W, et al: High expression levels of the D686N Parkinson's disease mutation in VPS35 induces α-synuclein-dependent toxicity in yeast. Mol Med Rep 16: 254-262, 2017.
APA
Huang, Y., Chen, X., He, X., Guo, C., Sun, X., Liang, F. ... Pei, Z. (2017). High expression levels of the D686N Parkinson's disease mutation in VPS35 induces α-synuclein-dependent toxicity in yeast. Molecular Medicine Reports, 16, 254-262. https://doi.org/10.3892/mmr.2017.6551
MLA
Huang, Y., Chen, X., He, X., Guo, C., Sun, X., Liang, F., Long, S., Lu, X., Feng, L., Guo, W., Zeng, Y., Pei, Z."High expression levels of the D686N Parkinson's disease mutation in VPS35 induces α-synuclein-dependent toxicity in yeast". Molecular Medicine Reports 16.1 (2017): 254-262.
Chicago
Huang, Y., Chen, X., He, X., Guo, C., Sun, X., Liang, F., Long, S., Lu, X., Feng, L., Guo, W., Zeng, Y., Pei, Z."High expression levels of the D686N Parkinson's disease mutation in VPS35 induces α-synuclein-dependent toxicity in yeast". Molecular Medicine Reports 16, no. 1 (2017): 254-262. https://doi.org/10.3892/mmr.2017.6551