Abstract

Dendrite regulation by the mitochondrial kinase PINK1: Implications for PD/LBD PROJECT SUMMARY. Synaptic loss is a major structural correlate of dementia, and reduced spine density is observed in the Parkinson's disease (PD)-Lewy body dementia (LBD) disease spectrum. Autosomal recessive mutations in PTEN-induced kinase 1 (PINK1) cause early-onset PD and PD with dementia (PDD). Heterozygous carriers also exhibit cognitive-executive dysfunction and limbic-cortical degeneration. As PINK1 is neuroprotective in a wide range of genetic and toxin-based models of neurodegeneration, studying its function in neurons may offer insights into potential therapeutic strategies. Endogenous PINK1 exists in both mitochondrial and cytosolic compartments. Our prior studies show that these pools of PINK1 play divergent roles in regulating mitochondrial fission-fusion, mitophagy, calcium homeostasis and dendritic morphogenesis. Moreover, loss of PINK1 results in dendritic simplification in cortical and midbrain neurons. We hypothesize that PINK1 interacts with cytosolic targets to regulate neuron differentiation and synaptodendritic complexity. Using mass spectrometry, we identified novel PINK1-interacting proteins, which preliminary studies implicate in neurite extension or neuronal transport. We will study the role of these novel PINK1 interactions in regulating dendritogenesis and mitochondrial transport into dendrites using primary cortical and midbrain neurons, differentiated neuronal cell lines and PINK1 knockout and control mice. The potential role of phosphorylation and the impact of PD-linked mutations on these neuron-specialized functions of PINK1 will be analyzed. The neuroprotective potential of upregulating downstream pathway components will be tested in vitro and in Pink1-/- mice. A better understanding of novel PINK1-driven mechanisms that act to prevent dendritic simplification may yield valuable insights for neuroprotection in the PD-LBD disease spectrum.

Public Health Relevance

. Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) contribute to a recessive form of Parkinson's disease with early cognitive dysfunction. In this proposal, we will focus on mechanisms by which PINK1 promotes the elaboration and maintenance of an extended network of thin cellular extensions that function as communication cables in the brain. We will examine the role of novel proteins that interact with PINK1, and how disease-causing mutations in PINK1 affect these interactions. Completion of this study will enhance understanding of mitochondrial and cytosolic mechanisms by which PINK1 regulates these structural elements, which are essential for brain cell health and function. This may help identify new strategies to prevent or slow neurodegeneration in Parkinson's disease and related dementias.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS101628-04
Application #
9973247
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Cheever, Thomas
Project Start
2017-09-01
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15260