Effect of parkin levels and function on presynaptic mitochondrial bioenergetics and proteome dynamics: Role in Parkinson's Disease
Kelly L. Stauch1, Anna L. Fangmeier1, Steven A. Totusek1, and Howard S. Fox1
1Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
Loss-of-function mutations in the gene encoding the Parkin protein lead to juvenile-onset autosomal recessive forms of Parkinson's disease (PD), a neurodegenerative disease characterized by motor symptoms that reflect the selective loss of dopaminergic (DA) neurons of the substantia nigra pars compacta and the associated loss of DA inputs into the striatum. Parkin, a multifaceted E3 ubiquitin ligase, has been attributed to a variety of cellular functions, such as elimination of damaged mitochondria (mitophagy) and degradative ubiquitination of single substrates. Additionally, Parkin is implicated to play a role in the regulation of synaptic function. In fact, Parkin plays an important neuroprotective role in response to numerous cellular stressors including mitochondrial toxins. Overexpression of Parkin can also protect cells from mitochondrial dysfunction caused by inactivation of PINK1 or DJ-1, two proteins associated with PD that are involved in regulating mitochondrial function, mitophagy, and resistance to oxidative stress. Taken together, these findings suggest that Parkin functions as a protective agent through mitochondrial protection and overexpression or activation of Parkin may provide a novel therapeutic strategy for PD. Therefore, we have examined the impact of Parkin deficiency, overexpression, and activation (i.e. W402A mutation, which increases auto-ubiquitination activity) in mice on several parameters of mitochondrial health in the brain. Functional analysis revealed alterations in Parkin augment nerve terminal bioenergetics. Taken together with mass spectrometry-based protein turnover findings, our results suggest that the observed perturbations in synaptic mitochondrial proteome dynamics may contribute to the energy status at the synapse. This work highlights the relationship of Parkin protein levels and activity with synaptic mitochondrial function, proteome composition, and protein turnover dynamics.