Congratulations to Drs., , , , , and on the publication of “Rab8a protects against alpha-synuclein toxicity in a rat model of Parkinsonism” in the April 24th supplement to Neurology.
Objective: To test this effect viral expression of Rab8a on α-synuclein (αS) toxicity in a rat model of Parkinsonism.
Background: Accumulation of αS results in endoplasmic reticulum stress, intracellular protein/vesicular trafficking deficits, and cytotoxicity that contribute to Parkinson disease (PD). αS in Lewy body disorders interacts with Rab GTPase proteins that have critical functions in intracellular trafficking, transport, and exocytosis. Recently, several Rab GTPases have been shown to be phosphorylated by the lucine-rich repeat kinase 2 (LRRK2) supporting a role in PD. αS-related trafficking deficits, vesicle accumulation, and cytotoxicity can be rescued by expression of specific Rab GTPase proteins such as Rab8a. We have shown that Rab8a expression potently reduces αS levels and oligomer formation, and rescues Golgi fragmentation, supporting a potential neuroprotective role. These data suggest that accrual of αS interferes with the normal function of trafficking proteins and that overexpression of certain Rab GTPases, such as Rab8a, may mitigate αS toxicity.
Design/Methods: Adult rats were unilaterally injected in the substantia nigra (SN) with recombinant adeno-associated virus (rAAV) serotype 2/8, expressing human αS or empty vector plus or minus Rab8a. At 8 weeks post injection, rats were sacrificed and brains extracted for histological and biochemical analyses.
Results: There was robust co-expression of αS and Rab8a in animals that received combined rAAV injection.
Expression of αS alone caused significant (>60%) TH cell loss in SN and accumulation of pathological phosphorylated αS. However, co-expression with Rab8a did not appear to rescue αS-induced TH cell loss in the SN. Despite these findings, viral expression of Rab8a reduced αS levels in midbrain tissues and partially rescued TH expression in the striatum. These findings correlated with increase/normalization of striatal dopamine and metabolites.
Conclusions: These preliminary findings provide evidence that targeted viral-mediated Rab8a overexpression can rescue αS-mediated nigrostriatal toxicity in a rat model of Parkinsonism.