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Year 5 Pilot Projects

Contribution of Locus Coeruleus-Ventral Periaqueductal Gray Circuit Dysfunction to Sleepiness in Parkinson’s Disease

Kirsten A. Porter-Stransky, Ph.D., Principal Investigator; David Weinshenker, Ph.D., Co-investigator

Parkinson’s disease (PD) causes a number of debilitating, non-motor symptoms in addition to the iconic motor impairments.  Sleep disorders, especially excessive sleepiness, is one of the most commonly reported non-motor symptoms of PD that significantly reduces the quality of life of PD patients; however, the neurobiological mechanisms underlying excessive sleepiness in PD remain to be elucidated.   In the proposed experiments, we will investigate an understudied circuit that may mediate the excessive sleepiness in PD: noradrenergic projections from the locus coeruleus (LC) to the ventral periaqueductal gray (vPAG).  While degeneration of the dopaminergic substantia nigra pars compacta (SN) is considered the hallmark neuropathology of PD, an underappreciated facet of the disease is the catastrophic loss of LC neurons that actually precedes SN cell death.  It is well established that the LC promotes arousal, and vPAG DA neurons also have wake-promoting properties.  Unlike traditional SN DA neurons, vPAG DA neurons remain relatively intact in PD but likely have reduced function due to reduced noradrenergic inputs from the degenerating LC, resulting in sleepiness.  Utilizing a combination of genetically engineered mice, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), and site-specific behavioral pharmacology, we will test the hypothesis that attenuated noradrenergic transmission from the LC to the vPAG, and the resulting reduction of vPAG DA neuronal activity, mediates the excessive sleepiness that occurs in PD.  In Aim 1 we will test whether LC-derived neurotransmission at α1 noradrenergic receptors in the vPAG promotes arousal, measured by locomotor activity and latency to fall asleep. In Aim 2 we will examine whether direct activation of dopaminergic vPAG neurons can promote arousal in a mouse model of PD-associated sleepiness.  Together, these experiments will provide novel insight into the contribution of LC-vPAG interactions to PD-like sleepiness and form the basis for a future collaborative grant to comprehensively study this circuit.

Novel neuroprotective mechanisms against mitochondria dysfunction and neurodegeneration in Parkinson disease

Lian Li, Ph.D., Principal Investigator

Parkinson disease (PD) is the second most common neurodegenerative disease, with a prevalence of 1-2% over the age of 65. While the pathogenic mechanisms that cause neurodegeneration in PD remain unclear, mitochondrial dysfunction is strongly implicated in PD pathogenesis. Loss-of-function mutations in E3 ubiquitin-protein ligase parkin are a major cause of familial PD, and oxidative/nitrosative stress-induced damage to parkin is associated with sporadic PD. Elucidation of parkin-independent neuroprotective mechanisms is highly significant because the knowledge will promote development of new therapies for combating neurodegeneration in PD, particularly those PD cases with impaired parkin function. Mitophagy mediates selective clearance of dysfunctional mitochondria and plays an important role in neuroprotection against mitochondrial dysfunction. At present, our knowledge of the signaling pathways and regulatory mechanisms that control mitophagy is limited. Although parkin-mediated ubiquitin signaling has been shown to regulate mitophagy, emerging evidence indicates that there is yet unidentified, parkin-independent pathway(s) for clearance of dysfunctional mitochondria. In this pilot project, we propose to follow up on our preliminary data and study a novel E3 ubiquitin-protein ligase and its role in regulating parkin-independent.