Objective: To assess the effects of rapamycin on motor behavior, α-synuclein burden and surrogate markers of neurodegeneration in a transgenic mouse model of multiple system atrophy (MSA).

Background: Growing evidence suggests impairment of the autophagy-lysosomal pathway in MSA. Since this pathway has a major role in the degradation of α-synuclein, its impaired function may contribute to the accumulation of α-synuclein in glial cytoplasmic inclusions in MSA. The mammalian target of rapamycin complex 1 (mTORC1) is a key protein complex regulating autophagy. Rapamycin is an mTORC1 inhibitor that enhances autophagy, by increasing autophagosomes and boosting lysosomal biogenesis. We here assessed if rapamycin exerts neuroprotective effects by enhancing autophagic α-synuclein clearance in a transgenic mouse model of MSA.

Methods: Wild-type (WT) and PLP-SYN transgenic mice were fed either with normal food or food enriched with 14mg/kg of rapamycin for 16 weeks since age 6 weeks. Motor behavior was assessed at baseline and every 4 weeks until termination. Histopathological analysis included cell survival in the substantia nigra pars compacta (SNpc) as assessed by the number of tyrosine hydroxylase and Nissl positive neurons, and the amount of α-synuclein aggregates in oligodendrocytes in the SNpc and the striatum after incubation of sections with or without proteinase K. Additional immunoblotting was performed to measure α-synuclein load.

Results: Rapamycin was safe and well-tolerated. There was no difference in motor performance between groups. As expected, placebo-treated PLP-SYN mice showed dopaminergic cell loss in the SNpc compared to WT mice. Rapamycin provided partial neuroprotection since the number of Nissl positive neurons in the SNpc was similar compared to WT mice, while the number of tyrosine hydroxylase positive neurons was significantly lower and not different from placebo-treated PLP-SYN mice. Rapamycin also significantly reduced the amount of α-synuclein aggregates in the SNpc, while only a trend was observed for the striatum.

Conclusions: Rapamycin partially rescued neurons in the SNpc, although they remained dysfunctional as suggested by the down-regulated tyrosine hydroxylase expression. The partial rescue was paralleled by a positive effect on the amount of α-synuclein aggregates.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rapamycin-for-treating-msa-a-preclinical-proof-of-concept-study/