Thursday, November 21, 2024
11/21/2024
Abstract The complex and prolonged disease course exhibited by Parkinson’s disease (PD) first starts with non-motor disturbances and then slowly progresses to mild-to-moderate motor deficits, ultimately inflicting severe motor and cognitive deficits. Although pathophysiological mechanisms underlying various stages of the disease have yet to be characterized, both mitochondrial dysfunction (MD) and neural oxidative stress (OS) have been identified as key pathological correlates in the progressive neurodegenerative process in PD. While studying key oxidative signaling mechanisms that regulate susceptibility of the nigrostriatal dopamin(DA)ergic system to MD and oxidative damage, we unexpectedly discovered that protein kinase D1 (PKD1) is highly expressed in nigral DAergic neurons and that the kinase is rapidly activated during the early stages of oxidative insult to protect DAergic neurons against oxidative damage. Our mechanistic studies revealed that activated PKD1 rapidly translocates to both mitochondria and the nucleus of DAergic neurons. Our preliminary studies show that activated PKD1 likely enhances the transcription of key neuro-adaptive oxidative mechanisms involving enhanced PGC1-α, TFAM and BDNF signaling pathways. Thus, the goal of this study is to elucidate mitochondrial/nuclear events governing the PKD1-mediated compensatory protective response using cell and animal models of PD. The overarching hypothesis of our proposal is that the pro-survival kinase PKD1 is rapidly activated in nigral DAergic neurons during the initial stage of an oxidative insult and quickly translocates to mitochondria and nuclei to initiate cell survival signaling pathways. Its nuclear translocation initiates key pro- survival transcriptional machinery responsible for PGC1-α, TFAM and BDNF upregulation, leading to enhanced mitochondrial biogenesis and neurotrophic support in DAergic neurons. Mitochondrial translocation of PKD1 improves mitochondrial function by regulating mitochondrial quality control (MQC). Thus, PKD1 serves as a key ‘compensatory adaptive switch’ in nigral DAergic neurons. To test this, we will systematically pursue the following specific aims: (i) characterize PKD1 activation and nuclear/mitochondrial translocation and its functional relevance in cell culture and animal models of PD; (ii) characterize the downstream pro-survival signaling pathways activated by PKD1 mitochondrial/nuclear translocation in DAergic neurons; and (iii) validate PKD1 as a therapeutic target of PD and examine the translational potential of a novel PKD1 activator. We will use multiple model systems and state-of-the-art cellular, histological and neurochemical approaches to achieve these specific aims. Our multifaceted approach to harness the PKD1 adaptive signaling mechanisms that promote DAergic neuronal survival will enable us to devise a novel translational strategy capable of intervening early in the course of disease progression in PD.
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