Genetic or pharmacological activation of the Drosophila PGC-1α ortholog spargel rescues the disease phenotypes of genetic models of Parkinson’s disease

• Published in: Neurobiology of aging Vol. 55; pp. 33 - 37
• Main Authors: Ng, Chee-Hoe, Basil, Adeline H, Hang, Liting, Tan, Royston, Goh, Kian-Leong, O’Neill, Sharon, Zhang, Xiaodong, Yu, Fengwei, Lim, Kah-Leong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2017
• Subjects: AMP-Activated Protein Kinases - metabolism; AMP-Activated Protein Kinases - physiology; Animals; Disease Models, Animal; Drosophila - genetics; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Drosophila Proteins - physiology; Gene Expression - drug effects; Gene Silencing; Internal Medicine; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Mitochondria; Models, Genetic; Molecular Targeted Therapy; Neurology; Neuroprotection; Neuroprotective Agents; Organelle Biogenesis; Parkin; Parkinson Disease - genetics; Parkinson Disease - prevention & control; Parkinson Disease - therapy; Parkinson's disease; PGC-1α; Phenotype; Positive Transcriptional Elongation Factor B - genetics; Positive Transcriptional Elongation Factor B - metabolism; Positive Transcriptional Elongation Factor B - physiology; PQQ Cofactor - pharmacology; Ubiquitin-Protein Ligases - genetics; Neuroprotection; Mitochondria; PGC-1α; Parkinson's disease; Parkin
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2017.03.017

Abstract Despite intensive research, the etiology of Parkinson’s disease (PD) remains poorly understood and the disease remains incurable. However, compelling evidence gathered over decades of research strongly support a role for mitochondrial dysfunction in PD pathogenesis. Related to this, PGC-1α, a key regulator of mitochondrial biogenesis, has recently been proposed to be an attractive target for intervention in PD. Here, we showed that silencing of expression of the Drosophila PGC-1α ortholog spargel results in PD-related phenotypes in flies and also seem to negate the effects of AMPK activation, which we have previously demonstrated to be neuroprotective, i.e. AMPK-mediated neuroprotection appears to require PGC-1α. Importantly, we further showed that genetic or pharmacological activation of the Drosophila PGC-1α ortholog spargel is sufficient to rescue the disease phenotypes of Parkin and LRRK2 genetic fly models of PD, thus supporting the proposed use of PGC-1α-related strategies for neuroprotection in PD.