Synaptic dysfunction in genetic models of Parkinson's disease: a role for autophagy?
The past decade in Parkinson's disease (PD) research has been punctuated by numerous advances in understanding genetic factors that contribute to the disease. Common to most of the genetic models of Parkinsonian neurodegeneration are pathologic mechanisms of mitochondrial dysfunction, secretory vesicle dysfunction and oxidative stress that likely trigger common cell death mechanisms. Whereas presynaptic function is implicated in the function/dysfunction of α-synuclein, the first gene shown to contribute to PD, synaptic function has not comprised a major focus in most other genetic models. However, recent advances in understanding the impact of mutations in parkin and LRRK2 have also yielded insights into synaptic dysfunction as a possible early pathogenic mechanism. Autophagy is a common neuronal response in each of these genetic models of PD, participating in the clearance of protein aggregates and injured mitochondria. However, the potential consequences of autophagy upregulation on synaptic structure and function remain unknown. In this review, we discuss the evidence that supports a role for synaptic dysfunction in the neurodegenerative cascade in PD, and highlight unresolved questions concerning a potential role for autophagy in either pathological or compensatory synaptic remodeling. This article is part of a Special Issue entitled "Autophagy and protein degradation in neurological diseases."
Department of Pathology, Division of Neuropathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Edward D
ED
Plowey
Charleen T
CT
Chu
D000818:Animals; D001343:Autophagy / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010300:Parkinson Disease / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D013569:Synapses / Q000235:genetics* / Q000473:pathology* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics
C497604:SNCA protein, human; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases