Peer-Reviewed Journal Details
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Morales-Prieto N;Bevans R;O'Mahony A;Barron A;Giles Doran C;McCarthy E;Concannon RM;Goulding SR;McCarthy CM;Collins LM;Sullivan AM;O'Keeffe GW;
2024
March
Aging Cell
Human a-synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal ageing.
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Parkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and a-synuclein (aSyn) accumulation. Age is the biggest risk factor for PD and may create a vulnerable pre-parkinsonian state, but the drivers of this association are unclear. It is known that ageing increases aSyn expression in DA neurons and that this may alter molecular processes that are central to maintaining nigrostriatal integrity. To model this, adult female Sprague-Dawley rats received a unilateral intranigral injection of adeno-associated viral (AAV) vector carrying wild-type human aSyn (AAV-aSyn) or control vector (AAV-Null). AAV-aSyn induced no detrimental effects on motor behaviour, but there was expression of human wild-type aSyn 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-aSyn 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 in SH-SY5Y cells. Furthermore, experiments in SH-SY5Y cells revealed that SKOR1 overexpression impaired neurite growth to the same extent as aSyn, and inhibited BMP-SMAD-dependent transcription, a pathway that promotes DA neuronal survival and growth. Given the normal influence of ageing on DA neuron loss in human SN, the extent of aSyn-induced SKOR1 expression may influence whether an individual undergoes normal nigrostriatal ageing or reaches a threshold for prodromal PD. This provides new insight into mechanisms through which ageing-related increases in aSyn may influence molecular mechanisms important for the maintenance of neuronal integrity.
1474-9726
10.1111/acel.14155
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