| First Author | Ryan BJ | Year | 2021 |
| Journal | J Neurosci | Volume | 41 |
| Issue | 16 | Pages | 3731-3746 |
| PubMed ID | 33563726 | Mgi Jnum | J:313796 |
| Mgi Id | MGI:6707754 | Doi | 10.1523/JNEUROSCI.1478-20.2021 |
| Citation | Ryan BJ, et al. (2021) REST Protects Dopaminergic Neurons from Mitochondrial and alpha-Synuclein Oligomer Pathology in an Alpha Synuclein Overexpressing BAC-Transgenic Mouse Model. J Neurosci 41(16):3731-3746 |
| abstractText | 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-synuclein 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-synuclein 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-synuclein oligomers and mitochondrial damage, and displayed REST target gene dysregulation. Furthermore, CRISPR-mediated REST KO induced mitochondrial dysfunction and impaired mitophagy in vitro Conversely, REST overexpression attenuated mitochondrial toxicity and mitochondrial morphology disruption through the transcription factor PGC-1alpha. Finally, decreased alpha-synuclein oligomer accumulation and mitochondrial dysfunction in mice correlated with nuclear REST and PGC-1alpha 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.SIGNIFICANCE STATEMENT Understanding early Parkinsonian pathophysiology through studies of advanced preclinical models is fundamental to the translation of disease-modifying therapies. Here we show disease-relevant levels of alpha-synuclein expression in mice leads to accumulation of alpha-synuclein oligomers in the absence of overt aggregation, and mitochondrial dysfunction in dopaminergic neurons lacking the RE1 Silencing Transcription Factor. Our findings identify the mechanism of action of RE1 Silencing Transcription Factor and PGC-1alpha as mediators of dopaminergic vulnerability in alpha-synuclein BAC-transgenic mice and induced pluripotent stem cell-derived dopaminergic cultures, highlighting their potential as therapeutic targets. |
