Research ArticleParkinson’s Disease

PGC-1α, A Potential Therapeutic Target for Early Intervention in Parkinson’s Disease

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Science Translational Medicine  06 Oct 2010:
Vol. 2, Issue 52, pp. 52ra73
DOI: 10.1126/scitranslmed.3001059

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Getting to the Root of Parkinson’s Disease

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder that results in the loss of dopamine neurons in the substantia nigra of the brain. Degeneration of these movement-related neurons predictably causes rigidity, slowness of movement, and resting tremor, but patients also show cognitive changes. Although gene mutations have been identified in several families with PD, the cause of the more common sporadic form is not known. Certain environmental factors, such as exposure to the pesticide rotenone, combined with a genetic susceptibility, are thought to confer risk for developing PD. A key pathological feature seen in postmortem brain tissue from PD patients is Lewy bodies, neuronal inclusions containing clumps of the α-synuclein protein (which is mutated in familial PD), as well as damaged mitochondria. Taking a systems biology approach to pinpoint the root cause of PD, Zheng et al. now implicate altered activity of the master transcription factor PGC-1α and the genes it regulates in the early stages of PD pathogenesis.

To detect new sets of genes that may be associated with PD, the investigators did a meta-analysis of 17 independent genome-wide gene expression microarray studies that had been performed on a total of 322 postmortem brain tissue samples and 88 blood samples. The samples came from presymptomatic and symptomatic PD patients, as well as from control individuals who did not show any neurological deficits at autopsy. Nine genome-wide expression studies were conducted either on dopaminergic neurons obtained by laser capture from substantia nigra (three studies) or on substantia nigra homogenates (six studies). The authors then used a powerful tool called Gene Set Enrichment Analysis to sift through 522 gene sets (a gene set is a group of genes involved in one biological pathway or process). At the end of this tour-de-force analysis, they identified 10 gene sets that were all associated with PD.

The gene sets with the strongest association contained nuclear genes encoding subunits of the electron transport chain proteins found in mitochondria. These genes all showed decreased expression in substantia nigra dopaminergic neurons (obtained by laser capture) even in the earliest stages of PD. Furthermore, a second gene set associated with PD and also underexpressed in the earliest stages of PD encodes enzymes involved in glucose metabolism. These results are compelling because many studies have already implicated dysfunctional mitochondria and altered energy metabolism as well as defective glucose metabolism in PD. The authors realized that these gene sets had in common the master transcriptional regulator, PGC-1α, and surmised that disruption of PGC-1α expression might be a root cause of PD. They tested this hypothesis in cultured dopaminergic neurons from embryonic rat midbrain forced to express a mutant form of α-synuclein. Overexpression of PGC-1α in these neurons resulted in activation of electron transport genes and protection against neuronal damage induced by mutant α-synuclein. In other cultured neurons treated with rotenone, overexpression of PGC-1α also was protective, blocking pesticide-induced neuronal cell death. These exciting findings identify altered expression of PGC-1α and the genes it regulates as key players during early PD pathogenesis. This potential new target could be exploited therapeutically to interfere with the pathological process during the earliest stages before permanent damage and neuronal loss occurs.


  • Citation: B. Zheng, Z. Liao, J. J. Locascio, K. A. Lesniak, S. S. Roderick, M. L.Watt, A. C. Eklund, Y. Zhang-James, P. D. Kim, M. A. Hauser, E. Grünblatt, L. B. Moran, S. A. Mandel, P. Riederer, R. M. Miller, H. J. Federoff, U. Wüllner, S. Papapetropoulos, M. B. Youdim, I. Cantuti-Castelvetri, A. B. Young, J. M. Vance, R. L. Davis, J. C. Hedreen, C. H. Adler, T. G. Beach, M. B. Graeber, F. A. Middleton, J.-C. Rochet, C. R. Scherzer, the Global PD Gene Expression (GPEX) Consortium, PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease.. Sci. Transl. Med. 2, 52ra73 (2010).

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