What have we learned from Drosophila models of Parkinson's disease?
Parkinson's disease (PD) is characterized clinically by motor symptoms such as resting tremor, slowness of movement, rigidity, and postural instability, and pathologically by the degeneration of multiple neuronal types, including, most notably, dopaminergic (DA) neurons in the substantia nigra. Current medical treatment for PD focuses on dopamine replacement, but dopamine replacement ultimately fails and has little effect on a variety of dopamine-independent symptoms both within and outside the nervous system. To develop new therapies, we need to aim at alleviating widespread cellular defects in addition to those focusing on DA neuronal survival. Recent observations in Drosophila have provided important insights into the cellular basis of PD pathogenesis through the demonstration that two genes associated with familial forms of PD, pink1 and parkin, function in a common pathway. In this pathway, pink1 functions upstream of parkin to regulate mitochondrial fission/fusion dynamics and normal mitochondrial function. Subsequent observations in both fly and mammalian systems show that these proteins are important for sensing mitochondrial damage and recruiting damaged mitochondria to the quality control machinery for subsequent removal. This chapter reviews these findings, as well as studies of DJ-1 and Omi/HtrA2, two additional genes associated with PD that have also been implicated to regulate mitochondrial function. The chapter ends by discussing how Drosophila can be used to probe further the functions of pink1 and parkin and the regulation of mitochondrial quality more generally. In addition to PD, defects in mitochondrial function are associated with normal aging and with many diseases of aging. Thus, insights gained from the studies of mitochondrial dynamics and quality control in Drosophila are likely to be of general significance.
Guo
Ming
M
Department of Neurology, Brain Research Institute, David Geffen School of Medicine, Los Angeles, CA, USA. mingfly@ucla.edu
D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology; D004330:Drosophila / Q000235:genetics* / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics; D006801:Humans; D008928:Mitochondria / Q000473:pathology; D009474:Neurons / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D000099202:PTEN-Induced Putative Kinase
D004298:Dopamine; D029721:Drosophila Proteins; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase; C487430:park protein, Drosophila