Therapeutic approaches to mitochondrial dysfunction in Parkinson's disease.
A large body of evidence from postmortem brain tissue and genetic analysis in humans, as well as biochemical and pathological studies in animal models of neurodegeneration suggest that mitochondrial dysfunction is a key pathological mechanism in Parkinson's Disease (PD). Mitochondrial dysfunction leads to oxidative stress, damage to mitochondrial DNA, mitochondrial DNA deletions, altered mitochondrial morphology, alterations in mitochondrial fission and fusion and ultimately neuronal demise. Therapeutic approaches targeting mitochondrial dysfunction and oxidative damage, therefore, hold great promise in PD. A number of agents, which target energy metabolism, are presently in therapeutic trials in PD. Both creatine and Coenzyme Q10 (CoQ10) are being tested in phase III clinical trials. In addition, preclinical studies in animal models have shown efficacy of mitochondrial-targeted antioxidants and the SS peptides. A promising approach for increasing antioxidant defenses is to transcriptionally increase the activity of the Nrf2/ARE pathway, which activates transcription of anti-inflammatory and antioxidant genes. A number of agents including sulforaphane, curcumin and triterpenoids have been shown to activate this pathway and to produce neuroprotective effects. Lastly, newly identified therapeutic targets include peroxisomal proliferator activated receptor gamma-coactivator (PGC-1alpha) and sirtuins. These pathways provide promise for future therapeutic developments in the treatment of PD.
Beal
M Flint
MF
Department of Neurology & Neuroscience, Weill Cornell Medical College, New York, NY 10065-4870, USA. fbeal@mail.med.cornell.edu
D000818:Animals; D017326:Clinical Trials, Phase III as Topic; D003401:Creatine / Q000494:pharmacology / Q000627:therapeutic use; D006360:Heat-Shock Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015395:Histocompatibility Antigens Class I / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D028361:Mitochondrial Diseases / Q000209:etiology* / Q000235:genetics / Q000628:therapy*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010300:Parkinson Disease / Q000150:complications* / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000494:pharmacology / Q000627:therapeutic use
D006360:Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D051267:NF-E2-Related Factor 2; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C032907:Q surface antigens; D014157:Transcription Factors; D003401:Creatine