Human α‐synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal ageing

Author:

Morales‐Prieto Noelia1,Bevans Rebekah1,O'Mahony Adam1,Barron Aaron12,Giles Doran Conor1,McCarthy Erin1,Concannon Ruth M.1,Goulding Susan R.1,McCarthy Cathal M.2,Collins Louise M.134,Sullivan Aideen M.145ORCID,O'Keeffe Gerard W.145ORCID

Affiliation:

1. Department of Anatomy and Neuroscience, School of Medicine University College Cork Ireland

2. Department of Pharmacology and Therapeutics, School of Medicine University College Cork Cork Ireland

3. Department of Physiology, School of Medicine University College Cork Cork Ireland

4. Parkinson's Disease Research Cluster (PDRC) University College Cork Cork Ireland

5. APC Microbiome Ireland University College Cork Cork Ireland

Abstract

AbstractParkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and α‐synuclein (αSyn) 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 αSyn 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 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 in SH‐SY5Y cells. Furthermore, experiments in SH‐SY5Y cells revealed that SKOR1 overexpression impaired neurite growth to the same extent as αSyn, 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 αSyn‐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 αSyn may influence molecular mechanisms important for the maintenance of neuronal integrity.

Funder

Science Foundation Ireland

Cure Parkinson's Trust

HORIZON EUROPE Marie Sklodowska-Curie Actions

Publisher

Wiley

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