Rest Protects Dopaminergic Neurons From Mitochondrial And A-Synuclein Oligomer Pathology In An Alpha Synuclein Overexpressing Bac-Transgenic Mouse Model (Vol 41, Pg 3731, 2021)

Alpha-synuclein pathology is associated with dopaminergic neuronal loss in the substantia nigra (SN) of Parkinson's patients. Working across human and mouse models, we investigated mechanisms by which the accumulation of soluble alpha-synudein oligomers leads to neurodegeneration. Biochemical analysis of the midbrain of alpha-synuclein overexpressing BAC-transgenic male and female mice revealed age- and region-dependent mitochondrial dysfunction and accumulation of damaged proteins downstream of the RE1 Silencing Transcription Factor (REST). Vulnerable SN dopaminergic neurons displayed low REST levels compared with neighboring protected SN GABAergic neurons, which correlated with the accumulation of alpha-synudein oligomers and disrupted mitochondrial morphology. Consistent with a protective role, REST levels were reduced in patient induced pluripotent stem cell-derived dopaminergic neurons carrying the SNCA-Triplication mutation, which accumulated alpha-synudein oligomers and mitochondrial damage, and displayed REST target gene dysregulation. Furthermore, CRISPR-mediated REST KO induced mitochondria! dysfunction and impaired mitophagy in vitro. Conversely, REST overexpression attenuated mitochondrial toxicity and mitochondrial morphology disruption through the transcription factor PGC-1 alpha. Finally, decreased alpha-synudein oligomer accumulation and mitochondrial dysfunction in mice correlated with nuclear REST and PGC-1 alpha in protected SN GABAergic neurons compared with vulnerable dopaminergic neurons. Our findings show that increased levels of alpha-synuclein oligomers cause dopaminergic neuronal-specific dysfunction through mitochondrial toxicity, which can be attenuated by REST in an early model of Parkinsonian pathology. These findings highlight REST as a mediator of dopaminergic vulnerability in PD.