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

Huang,Yi; Chen,Xiang; He,Xiaofei; Guo,Caifeng; Sun,Xicui; Liang,Fengyin; Long,Simei; Lu,Xilin; Feng,Luyang; Guo,Wenyuan; Zeng,Yixuan; Pei,Zhong

doi:10.3892/mmr.2017.6551

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
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Affiliations: Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China, Department of Neurology, Guangzhou Huiai Hospital, Guangzhou, Guangdong 510370, P.R. China
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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