title: Slowing of neurodegeneration in Parkinson's disease and Huntington's disease: future therapeutic perspectives.
abstract: Several important advances have been made in our understanding of the pathways that lead to cell dysfunction and death in Parkinson's disease and Huntington's disease. These advances have been informed by both direct analysis of the post-mortem brain and by study of the biological consequences of the genetic causes of these diseases. Some of the pathways that have been implicated so far include mitochondrial dysfunction, oxidative stress, kinase pathways, calcium dysregulation, inflammation, protein handling, and prion-like processes. Intriguingly, these pathways seem to be important in the pathogenesis of both diseases and have led to the identification of molecular targets for candidate interventions designed to slow or reverse their course. We review some recent advances that underlie putative therapies for neuroprotection in Parkinson's disease and Huntington's disease, and potential targets that might be exploited in the future. Although we will need to overcome important hurdles, especially in terms of clinical trial design, we propose several target pathways that merit further study. In Parkinson's disease, these targets include agents that might improve mitochondrial function or increase degradation of defective mitochondria, kinase inhibitors, calcium channel blockers, and approaches that interfere with the misfolding, templating, and transmission of α-synuclein. In Huntington's disease, strategies might also be directed at mitochondrial bioenergetics and turnover, the prevention of protein dysregulation, disruption of the interaction between huntingtin and p53 or huntingtin-interacting protein 1 to reduce apoptosis, and interference with expression of mutant huntingtin at both the nucleic acid and protein levels.
authors: Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK. Electronic address: a.schapira@ucl.ac.uk.
authors: Anthony H V
authors: AH
authors: Schapira
authors: Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.
authors: C Warren
authors: CW
authors: Olanow
authors: Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors: J Timothy
authors: JT
authors: Greenamyre
authors: Université de Bordeaux, Institut des Maladies Neurodégénératives, 33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, 33000 Bordeaux, France.
authors: Erwan
authors: E
authors: Bezard
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018696:Neuroprotective Agents; D017978:Receptors, Growth Factor; D011494:Protein Kinases