Rab1A over-expression prevents Golgi apparatus fragmentation and partially corrects motor deficits in an alpha-synuclein based rat model of Parkinson's disease.
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.
Neurodegenerative Studies Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
P G
PG
Coune
J C
JC
Bensadoun
P
P
Aebischer
B L
BL
Schneider
D000818:Animals; D001058:Apomorphine; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure*; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D005552:Forelimb / Q000503:physiopathology; D005822:Genetic Vectors / Q000502:physiology; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D020761:rab1 GTP-Binding Proteins / Q000378:metabolism*
D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase; D020761:rab1 GTP-Binding Proteins; D001058:Apomorphine