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Understanding the Interaction between LRRK2 and PINK1: Implications for Parkinson’s Disease

Cherra, Salvatore J. (2011) Understanding the Interaction between LRRK2 and PINK1: Implications for Parkinson’s Disease. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects nearly 1% of the US population over the age of 65. While PD is primarily a sporadic disease, roughly 10% of PD cases are due to genetic mutations, giving rise to familial forms of PD. Interestingly, mutations in two kinases, the leucine-rich repeat kinase 2 (LRRK2) and the PTEN-induced kinase 1 (PINK1), underlie two forms familial PD. Although the pathogenic mechanisms still remain unknown, many insights have been gained from investigating toxin insults and genetic mutations that cause parkinsonian phenotypes. Studies using neurotoxins and genetic mutations that underlie familial PD have implicated mitochondrial dysfunction in the pathogenesis of PD. This project sought to identify modes of neuroprotection that ameliorated the effects of LRRK2 mutations on neuronal and mitochondrial homeostasis. The mechanism of protein kinase A (PKA)-mediated neuroprotection was investigated in neurotoxin and genetic models of PD. This study also explored the mechanisms of PINK1-mediated neuroprotection. Activation of PKA prevented mutant LRRK2-induced neurite shortening by suppressing autophagy through the phosphorylation of the autophagy protein, the microtubule-associated protein light chain 3. This study also found that mutant LRRK2 causes mitochondrial degradation by autophagy in the dendrites of neurons, which led to shortening of the dendrites. PINK1 suppressed the autophagy induction elicited by mutant LRRK2 and prevented the mitochondrial degradation and neurite shortening. Furthermore, mutant LRRK2 caused a delay in calcium clearance after neuronal
depolarization. This prolonged elevation in intracellular calcium caused mitochondrial depolarization followed by degradation. Indeed, calcium chelation or inhibition of voltage-gated calcium channel restored calcium homeostasis and attenuated the mitochondrial degradation and dendrite shortening induced by LRRK2 mutations. Finally using immunoprecipitation and 2- dimensional gel electrophoresis, PINK1 was found to interact with and regulate the phosphorylation status of proteins that maintain mitochondrial polarization, energy production, and calcium buffering. Overall, these results indicate that autophagy modulation and restoration of mitochondrial homeostasis protects against mutant LRRK2. This study proposes that calcium imbalance, mitochondrial dysfunction, and autophagy dysregulation are early events in the pathogenesis of familial and sporadic PD and thus, are potential therapeutic targets for PD.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Cherra, Salvatore J.sac83@pitt.eduSAC83
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBowser,
Thesis AdvisorChu, Charleenctc4@pitt.eduCTC4
Committee MemberDay, Billybday@pitt.eduBDAY
Committee MemberKulich, Scottkulichsm@upmc.eduSKULICH
Committee MemberZarnegar, Rezarezazar@pitt.eduREZAZAR
Date: 2 December 2011
Date Type: Publication
Defense Date: 25 July 2011
Approval Date: 2 December 2011
Submission Date: 29 November 2011
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 104
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: PINK1 interacting proteins, mass spectrometry, phospho-proteomics
Date Deposited: 02 Dec 2011 20:35
Last Modified: 19 Dec 2016 14:38


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