Mitochondrial dysfunction and Parkinson’s disease genes: insights from Drosophila

Abstract

Parkinson’s disease (PD), one of the most common neurodegenerative disorders worldwide, currently lacks a cure. Although most PD cases occur sporadically, studies from rare genetic mutations give significant insights into addressing the pathological mechanism of not only familial PD, but also sporadic PD. Recent PD research focuses on generating genetic mutant animal models that recapitulate the features of human PD patients. Significant advances in PD research have resulted from studying Drosophila mutants of several identified PD-associated genes because they show strikingly visible phenotypes. In particular, previous studies with the Drosophila mutants parkin and PINK1, which are two common causative genes among PD familial forms, have suggested strongly that mitochondrial dysfunction is the prominent cause for the PD pathogenesis and that these two PD genes are in a common pathway, with Parkin downstream of PINK1. Recent genetic studies have revealed that the PINK1-Parkin pathway is involved in regulating the mitochondrial remodeling process. In addition, PINK1 was recently found to regulate the localization of Parkin through direct phosphorylation. Here, we briefly review these new and exciting findings in Drosophila PD models and discuss how using these models can further advance PD studies.

Silent Information Regulator 2 (Sir2) and Forkhead Box O (FOXO) Complement Mitochondrial Dysfunction and Dopaminergic Neuron Loss in Drosophila PTEN-induced Kinase 1 (PINK1) Null Mutant

“…4). These data clearly showed that Sir2 and FOXO have protective roles in DA neuron and the indirect flight muscle, tissues with high demand for ATP generated by mitochondria (48). Because these defects were observed in 15-or 30-day-old flies, some may argue that these defects in Sir2 or FOXO mutants result from premature aging induced by loss of two genes.…”

Life Span and Locomotor Activity Modification by Glucose and Polyphenols in Drosophila melanogaster Chronically Exposed to Oxidative Stress-stimuli: Implications in Parkinson’s Disease

“…parkin, DJ-1, PINK::see http://superfly.ucsd.edu for further information). This unique feature has already led to a better understanding of how these genes work in the human [15,16]. Second, the expression of PD related genes in Drosophila can be performed by using the binary GAL4-dependent upstream activating sequence (GAL4/UAS) system [17], thus providing an excellent tool to express pathological proteins in the fly 0 s brain (e.g.…”

Parkin Is Dispensable for Mitochondrial Function, but Its Ubiquitin Ligase Activity Is Critical for Macroautophagy and Neurotransmitters: Therapeutic Potential beyond Parkinson's Disease

“…Parkin mediates selective autophagy of dysfunctional mitochondria (mitophagy) as a result of loss of mitochondrial membrane potential or imbalance of mitochondrial dynamics [4,103,104,105,106]. Parkin interacts with PINK1 to control mitochondrial degradation [107], while PARKIN mutations prevent normal mitophagy [108].…”