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PGC-1? activity in nigral dopamine neurons determines vulnerability to ?-synuclein.

ABSTRACT: Mitochondrial dysfunction and oxidative stress are critical factors in the pathogenesis of age-dependent neurodegenerative diseases. PGC-1?, a master regulator of mitochondrial biogenesis and cellular antioxidant defense, has emerged as a possible therapeutic target for Parkinson's disease, with important roles in the function and survival of dopaminergic neurons in the substantia nigra. The objective of this study is to determine if the loss of PGC-1? activity contributes to ?-synuclein-induced degeneration.We explore the vulnerability of PGC-1? null mice to the accumulation of human ?-synuclein in nigral neurons, and assess the neuroprotective effect of AAV-mediated PGC-1? expression in this experimental model. Using neuronal cultures derived from these mice, mitochondrial respiration and production of reactive oxygen species are assessed in conditions of human ?-synuclein overexpression. We find ultrastructural evidence for abnormal mitochondria and fragmented endoplasmic reticulum in the nigral dopaminergic neurons of PGC-1? null mice. Furthermore, PGC-1? null nigral neurons are more prone to degenerate following overexpression of human ?-synuclein, an effect more apparent in male mice. PGC-1? overexpression restores mitochondrial morphology, oxidative stress detoxification and basal respiration, which is consistent with the observed neuroprotection against ?-synuclein toxicity in male PGC-1? null mice.Altogether, our results highlight an important role for PGC-1? in controlling the mitochondrial function of nigral neurons accumulating ?-synuclein, which may be critical for gender-dependent vulnerability to Parkinson's disease.

SUBMITTER: Ciron C

PROVIDER: S-EPMC4379693 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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PGC-1α activity in nigral dopamine neurons determines vulnerability to α-synuclein.

Ciron Carine C Zheng Lu L Bobela Wojciech W Knott Graham W GW Leone Teresa C TC Kelly Daniel P DP Schneider Bernard L BL

Acta neuropathologica communications 20150401

<h4>Introduction</h4>Mitochondrial dysfunction and oxidative stress are critical factors in the pathogenesis of age-dependent neurodegenerative diseases. PGC-1α, a master regulator of mitochondrial biogenesis and cellular antioxidant defense, has emerged as a possible therapeutic target for Parkinson's disease, with important roles in the function and survival of dopaminergic neurons in the substantia nigra. The objective of this study is to determine if the loss of PGC-1α activity contributes t ...[more]

PMID: 25853296

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Project description:Human studies and preclinical models of Parkinson's disease implicate the involvement of both the innate and adaptive immune systems in disease progression. Further, pro-inflammatory markers are highly enriched near neurons containing pathological forms of alpha synuclein (?-syn), and ?-syn overexpression recapitulates neuroinflammatory changes in models of Parkinson's disease. These data suggest that ?-syn may initiate a pathological inflammatory response, however the mechanism by which ?-syn initiates neuroinflammation is poorly understood. Silencing endogenous ?-syn results in a similar pattern of nigral degeneration observed following ?-syn overexpression. Here we aimed to test the hypothesis that loss of ?-syn function within nigrostriatal neurons results in neuronal dysfunction, which subsequently stimulates neuroinflammation. Adeno-associated virus (AAV) expressing an short hairpin RNA (shRNA) targeting endogenous ?-syn was unilaterally injected into the substantia nigra pars compacta (SNc) of adult rats, after which nigrostriatal pathology and indices of neuroinflammation were examined at 7, 10, 14 and 21 days post-surgery. Removing endogenous ?-syn from nigrostriatal neurons resulted in a rapid up-regulation of the major histocompatibility complex class 1 (MHC-1) within transduced nigral neurons. Nigral MHC-1 expression occurred prior to any overt cell death and coincided with the recruitment of reactive microglia and T-cells to affected neurons. Following the induction of neuroinflammation, ?-syn knockdown resulted in a 50% loss of nigrostriatal neurons in the SNc and a corresponding loss of nigrostriatal terminals and dopamine (DA) concentrations within the striatum. Expression of a control shRNA did not elicit any pathological changes. Silencing ?-syn within glutamatergic neurons of the cerebellum did not elicit inflammation or cell death, suggesting that toxicity initiated by ?-syn silencing is specific to DA neurons. These data provide evidence that loss of ?-syn function within nigrostriatal neurons initiates a neuronal-mediated neuroinflammatory cascade, involving both the innate and adaptive immune systems, which ultimately results in the death of affected neurons.

Dataset Information

PGC-1? activity in nigral dopamine neurons determines vulnerability to ?-synuclein.

Publications

PGC-1α activity in nigral dopamine neurons determines vulnerability to α-synuclein.

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