Dataset Information

Targeting ?-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations.

ABSTRACT: Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the ?-synuclein protein in the form of Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease. Most cases occur sporadically, but mutations in several genes, including SNCA, which encodes ?-synuclein, are associated with disease development. The discovery and development of therapeutic strategies to block cell death in Parkinson's disease has been limited by a lack of understanding of the mechanisms driving neurodegeneration. However, increasing evidence of multiple pivotal roles of ?-synuclein in the pathogenesis of Parkinson's disease has led researchers to consider the therapeutic potential of several strategies aimed at reduction of ?-synuclein toxicity. We critically assess the potential of experimental therapies targeting ?-synuclein, and discuss steps that need to be taken for target validation and drug development.

SUBMITTER: Dehay B

PROVIDER: S-EPMC5217462 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Publications

Targeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations.

Dehay Benjamin B Bourdenx Mathieu M Gorry Philippe P Przedborski Serge S Vila Miquel M Hunot Stephane S Singleton Andrew A Olanow C Warren CW Merchant Kalpana M KM Bezard Erwan E Petsko Gregory A GA Meissner Wassilios G WG

The Lancet. Neurology 20150603 8

Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the α-synuclein protein in the form of Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease. Most cases occur sporadically, but mutations in several genes, including SNCA, which encodes α-synuclein, are associated with disease development. The discovery and development of therapeutic strategies to block cell death in Parkinson's disease has been lim ...[more]

PMID: 26050140

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Project description:Advances in gerontology have yielded crucial insights into the molecular and biochemical aspects of the ageing process. The sirtuin pathway, which is most notable for its association with the anti-ageing effects of calorie restriction, has received particular attention, and pharmacological or transgenic upregulation of the sirtuin pathway has shown promising results in laboratory models of ageing. Alzheimer's disease is a neurodegenerative disease that is imposing an increasing burden on society, and is the leading cause of senile dementia worldwide. The lack of therapies for Alzheimer's disease provides a strong incentive for the development of an effective treatment strategy and, interestingly, research has uncovered a mechanism of action of the sirtuin pathway that might have therapeutic potential for Alzheimer's disease.SIRT1, one of the seven mammalian proteins of the sirtuin family of NAD(+)-dependent deacetylases, has recently been shown to attenuate amyloidogenic processing of amyloid-? protein precursor (APP) in cell culture studies in vitro and in transgenic mouse models of Alzheimer's disease. Mechanistically, SIRT1 increases ?-secretase production and activity through activation of the ?-secretase gene ADAM10. Because ?-secretase is the enzyme responsible for the non-amyloidogenic cleavage of APP, upregulation of ?-secretase shifts APP processing to reduce the pathological accumulation of the presumptive toxic A? species that results from ?-secretase and ?-secretase activity. Interestingly, the spatial patterns of A? deposition in the brain might correlate with increased aerobic glycolysis in those regions. Because aerobic glycolysis depletes cellular levels of NAD(+) (through a decreased NAD(+)/NADH ratio), it is possible that a corresponding downregulation of the NAD(+)-dependent sirtuin pathway contributes to the amyloidogenic processing of APP. WHERE NEXT?: The specific inhibition of A? generation by SIRT1 coupled with the potential link between aerobic glycolysis, NAD(+) depletion, and amyloidogenesis through the sirtuin pathway has translational implications. On the one hand, the possible underlying role of the sirtuin pathway in Alzheimer's disease onset and development might increase our understanding of this devastating condition. On the other hand, therapeutic upregulation of SIRT1 might provide opportunities for the amelioration of Alzheimer's-disease-type neuropathology through inhibition of amyloidogenesis. Ultimately, further analysis into both aspects is necessary if any progress is to be made.

Dataset Information

Targeting ?-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations.

Publications

Targeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations.

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