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bioRxiv · 10.1101/357624

Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway.

Park, J.-H.·Delenclos, M.·Faroqi, A. H.·DeMeo, N. N.·McLean, P.
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Abstract

The sirtuins are highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent enzymes that play a broad role in cellular metabolism and aging. Mitochondrial sirtuin 3 (SIRT3) is downregulated in aging and age-associated diseases such as cancer and neurodegeneration and plays a major role in maintaining mitochondrial function and preventing oxidative stress. Mitochondria dysfunction is central to the pathogenesis of Parkinson disease with mutations in mitochondrial-associated proteins such as PINK1 and parkin causing familial Parkinson disease. Here, we demonstrate that the presence of alpha-synuclein oligomers in mitochondria induce a corresponding decrease in mitochondrial SIRT3 activity and decreased mitochondrial biogenesis. We show that SIRT3 downregulation in the presence of alpha-synuclein accumulation is accompanied by increased phosphorylation of AMP-activated protein kinase (AMPK) and cAMP-response element binding protein (CREB), increased phosphorylation of dynamin-related protein 1(DRP1) and decreased levels of optic atrophy 1 (OPA1), which are indicative of impaired mitochondrial dynamics. Treatment with the AMPK agonist 5-aminoimidazole-4-carboxamide-1-{beta}-d-ribofuranoside (AICAR) restores SIRT3 expression and improves alpha-synuclein-induced mitochondrial dysfunction by decreasing oligomer formation. The accumulation of alpha-synuclein oligomers in mitochondria corresponds with SIRT3 downregulation not only in an experimental cellular model, but also in vivo in a rodent model of Parkinson's disease, and importantly in human post mortem brains with neuropathologically confirmed Lewy body disease (LBD). Taken together our findings suggest that pharmacologically increasing SIRT3 levels will counteract syn-induced mitochondrial dysfunction by normalizing mitochondrial bioenergetics. These data support a protective role for SIRT3 in Parkinson disease-associated pathways and reveals significant mechanistic insight into the interplay of SIRT3 and syn.

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Park, J.-H., Delenclos, M., Faroqi, A. H., DeMeo, N. N., McLean, P.. 2018-06-28. Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway.. https://doi.org/10.1101/357624

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