Rab1A Over-Expression Prevents Golgi Apparatus Fragmentation and Partially Corrects Motor Deficits in an Alpha-Synuclein Based Rat Model of Parkinson's Disease

Article type: Research Article

Authors: Coune, P.G. | Bensadoun, J.C. | Aebischer, P. | Schneider, B.L.

Affiliations: Neurodegenerative Studies Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

Note: [] Correspondence to: Patrick Aebischer, MD, EPFL SV BMI LEN, Station 19, CH 1015 Lausanne, Switzerland. Tel.: +41 (0)21 693 95 05; Fax : +41 (0)21 693 95 20; E-mail: [email protected]

Note: [] Correspondence to: Bernard Schneider, PhD, EPFL SV BMI LEN, Station 19, CH 1015 Lausanne, Switzerland. Tel.: +41 (0)21 693 95 19; Fax : +41 (0)21 693 95 20; E-mail: [email protected]

Abstract: Although the overabundance of human alpha-synuclein in nigral dopaminergic neurons is considered to play a pathogenic role in Parkinson's disease (PD), it remains unclear how alpha-synuclein leads to neuronal degeneration and motor symptoms. Here, we explored the effect of human alpha-synuclein in the rat substantia nigra following AAV-mediated gene delivery inducing a moderate loss of dopaminergic neurons together with motor impairments. A significant fraction of the surviving nigral neurons were found to express human αSyn and displayed a pathological fragmentation of the Golgi apparatus. This observation prompted further investigation on the role of the secretory pathway, in particular at the ER/Golgi level, in alpha-synuclein toxicity. To address this question, we co-expressed human alpha-synuclein with Rab1A, a regulator of ER-to-Golgi vesicular trafficking, and found a significant reduction of Golgi fragmentation. Rab1A did not protect the dopaminergic neurons from the alpha-synuclein-induced degeneration that occurred within several months following vector injection. However, we observed in animals co-expressing Rab1A an improvement of motor behavior that correlates with the rescue of normal Golgi morphology in alpha-synuclein-expressing dopaminergic neurons. The non-prenylable mutant Rab1A-DeltaCC did not produce any of the effects observed with the wild-type form of Rab1A, linking the protective role of Rab1A with its activity in ER-to-Golgi vesicular trafficking. In conclusion, Rab1A can rescue the Golgi fragmentation caused by the overabundance of alpha-synuclein in nigral dopaminergic neurons, improving the ability of the surviving neurons to control motor function in hemiparkinsonian animals.

Keywords: Alpha-synuclein, Rab1A, Golgi apparatus, Parkinson's disease, motor behavior, adeno-associated viral vector, substantia nigra

DOI: 10.3233/JPD-2011-11058

Journal: Journal of Parkinson's Disease, vol. 1, no. 4, pp. 373-387, 2011