Parkinson's disease, insulin resistance and novel agents of neuroprotection

• Published in: Brain (London, England : 1878) England : 1878), 2013-02, Vol.136 (Pt 2), p.374-384
• Main Authors: AVILES-OLMOS, Iciar, LIMOUSIN, Patricia, LEES, Andrew, FOLTYNIE, Thomas
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Animals; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diabetes mellitus; Diabetes Mellitus, Type 2 - epidemiology; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - prevention & control; Disease resistance; Electron transport; Enzymes; Epidemiology; Glucose metabolism; Humans; Huntington's disease; Insulin; Insulin Resistance - physiology; Medical sciences; Mitochondria; Movement disorders; Neurodegenerative diseases; Neurology; Neuroprotection; Neuroprotective agents; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Parkinson Disease - drug therapy; Parkinson Disease - epidemiology; Parkinson Disease - metabolism; Parkinson's disease; Peroxisome proliferator-activated receptors; pioglitazone
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/aws009

Multiple avenues of research including epidemiology, molecular genetics and cell biology have identified links between Parkinson's disease and type 2 diabetes mellitus. Several recent discoveries have highlighted common cellular pathways that potentially relate neurodegenerative processes with abnormal mitochondrial function and abnormal glucose metabolism. This includes converging evidence identifying that peroxisome proliferator activated receptor gamma coactivator 1-α, a key regulator of enzymes involved in mitochondrial respiration and insulin resistance, is potentially pivotal in the pathogenesis of neurodegeneration in Parkinson's disease. This evidence supports further study of these pathways, most importantly to identify neuroprotective agents for Parkinson's disease, and/or establish more effective prevention or treatment for type 2 diabetes mellitus. In parallel with these advances, there are already randomized trials evaluating several established treatments for insulin resistance (pioglitazone and exenatide) as possible disease modifying drugs in Parkinson's disease, with only preliminary insights regarding their mechanisms of action in neurodegeneration, which may be effective in both disease processes through an action on mitochondrial function. Furthermore, parallels are also emerging between these same pathways and neurodegeneration associated with Alzheimer's disease and Huntington's disease. Our aim is to highlight this converging evidence and stimulate further hypothesis-testing studies specifically with reference to the potential development of novel neuroprotective agents in Parkinson's disease.