Synaptic dysfunction in genetic models of Parkinson's disease: a role for autophagy?

Abstract

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."

Figure 1. Schematic diagram showing hypothetical links for LRRK2, parkin and α-synuclein in synaptic dysregulation

Parkin mutations have been reported by Helton and colleagues (Helton et al., 2008) to interrupt the ability of wild type parkin to pare excitatory synapses. Association of parkin and LRRK2 with elements of the secretory and endocytic pathways (see text) raise the possibility that they affect synaptic structure and function by regulating synaptic protein trafficking. LRRK2, which has been reported to interact with parkin (Smith et al., 2005), is hypothesized to induce the formation or stabilization of excitatory synapses. Downstream effects of LRRK2 and parkin mutations would thus increase vulnerability to synaptic glutamate stress (Helton et al., 2008) and could influence neuronal activity. Alterations in neuronal activity induce alterations in the distribution of α-synuclein, and thus may affect α-synuclein effects in the pre-synaptic terminal. Hypothetically, alterations in α-synuclein distribution and function could decrease pre-synaptic vesicle cycling to decrease dopaminergic oxidative stress and synaptic glutamate stress, but this function may be undermined by the propensity for α-synuclein to form cytosolic aggregates. The speculative linkages among these elements are indicated with question marks.