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Human α-synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal aging

ABSTRACT: Parkinson’s disease is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and intraneuronal accumulation of α-synuclein (αSyn) protein. Age is the biggest risk factor for Parkinson’s and has been suggested to create a vulnerable pre-parkinsonian state, but the drivers of this association are unclear. It is known that aging leads to increased αSyn expression in DA neurons and it is possible that this may alter molecular processes that are central to maintaining nigrostriatal integrity. To investigate this, adult female Sprague-Dawley rats received unilateral intranigral injection of adeno-associated viral (AAV) vector carrying wild-type human αSyn (AAV-αSyn) or control vector (AAV-Null). AAV-αSyn induced no detrimental effects on motor behaviour, but there was expression of human wild-type αSyn throughout the midbrain and ipsilateral striatum at 20 weeks post-surgery. Microarray analysis revealed that the gene most-upregulated in the ipsilateral SN of the AAV-αSyn group was the SKI Family Transcriptional Corepressor 1 (SKOR1). Bioenergetic state analysis of mitochondrial function found that SKOR1 overexpression reduced the maximum rate of cellular respiration. Furthermore, SKOR1 impaired neurite growth to the same extent as α-synuclein, and inhibited BMP-SMAD-dependent transcription, a pathway that promotes DA neuron survival and growth. Given the normal influence of ageing on DA neuron loss in human SN, the extent to which αSyn upregulates SKOR1 may influence whether an individual undergoes normal nigrostriatal ageing or reaches a threshold for prodromal PD. This provides new insight into mechanisms through which age-related changes may influence molecular mechanisms controlling neuronal integrity across the lifespan.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE252918 | GEO | 2024/08/08

REPOSITORIES: GEO

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Human α-synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal aging

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