- PROJECT 1: BIOLOGY OF PARKIN AND ITS ROLE IN PARKINSON'S DISEASE Parkinson's disease (PD) is a complex neurodegenerative disorder that is both sporadic and familial. Mutations in parkin are the most common cause of autosomal recessive PD. In sporadic PD dopaminergic, oxidative and nitrosative stress as well as c-Abl phosphorylation result in inhibition of parkin. Thus, loss of parkin function is elemental to both familial and sporadic PD. Parkin is an E3 ligase, this loss of function leads to accumulation of the substrates, AIMP2 and PARIS. We have found that AIMP2 expression leads to age dependent DA neurodegeneration due to parthanatos. And PARIS expression may lead to loss of mitochondrial quality control that promotes neurodegeneration. Our hypothesis is that parkin inactivation in sporadic PD by nitrosative/oxidative stress, and c-Abl activation leads to phosphorylation of parkin on Y143 (pY143 parkin) and inactivation followed by the accumulation of parkin substrates, loss of mitochondrial quality control and toxicity. In parallel, ?-synuclein is phosphorylated on Y39 (pY39 ?-synuclein) resulting in aggregation and subsequent toxicity. Since aggregated ?-synuclein can lead to mitochondrial dysfunction it creates a feed forward cycle.
Aim 1 : One of the unifying features of PD is mitochondrial dysfunction.
This aim will explore the inter- relationship of PARIS and mitochondrial dysfunction caused by mutations in parkin. We have shown that PARIS is an important pathophysiologic substrate of parkin in PD that transcriptionally represses PGC-1? a major transcriptional co-activator that regulates mitochondrial biogenesis and mitochondrial oxidant stress responses.
Aim 2 : Inactivation of parkin results in accumulation of both AIMP2 and PARIS. Expression of either AIMP2 or PARIS is sufficient to promote age dependent DA neurodegeneration. The sequence of events activated by PARIS and AIMP2 will be explored to determine if and how these two proteins interact to initiate the cell death program, parthanatos.
Aim 3 : We observe pY143 parkin and elevated AIMP2 and PARIS in A53T ?-synuclein transgenic mice that raises the question of whether parkin inactivation, PARIS and AIMP2 upregulation and PARP1 activation play a role in ?-synuclein induced neurodegeneration? This possibility will be explored with the ?-synuclein preformed fibrils (PFFs) model of PD.
Aim 4 : State-of-the-art technology including deep sequencing and SILAM (stable isotope labeling by amino acids in mammals) will be deployed to identify genes and proteins that are regulated by adult conditional knockout of parkin and their relationship to PARIS induction with the goal of identify nodal points in the signal cascade of neurodegeneration that can provide new targets for the treatment of PD.

Public Health Relevance

Loss of parkin function the most common cause of familial PD and is present in the majority of sporadic PD. Loss of parkin function leads to accumulation of parkin substrates, AIMP2 and PARIS that facilitate age dependent dopaminergic neuronal cell loss, possibly due to impairment of mitochondrial quality control. The goals of this project are to understand mechanistic signaling events that result in neurodegeneration due to loss of parkin function resulting in accumulation of PARIS and AIMP2.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
2P50NS038377-16
Application #
8882845
Study Section
Special Emphasis Panel (ZNS1-SRB-J (07))
Project Start
2014-09-30
Project End
2019-07-31
Budget Start
2014-09-30
Budget End
2015-07-31
Support Year
16
Fiscal Year
2014
Total Cost
$413,100
Indirect Cost
$158,100
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Siuda, Joanna; Jasinska-Myga, Barbara; Boczarska-Jedynak, Magdalena et al. (2014) Early-onset Parkinson's disease due to PINK1 p.Q456X mutation--clinical and functional study. Parkinsonism Relat Disord 20:1274-8
Fatokun, Amos A; Dawson, Valina L; Dawson, Ted M (2014) Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities. Br J Pharmacol 171:2000-16
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Martin, Ian; Kim, Jungwoo Wren; Lee, Byoung Dae et al. (2014) Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. Cell 157:472-85
Tsika, Elpida; Glauser, Liliane; Moser, Roger et al. (2014) Parkinson's disease-linked mutations in VPS35 induce dopaminergic neurodegeneration. Hum Mol Genet 23:4621-38
Pirooznia, Sheila K; Dawson, Valina L; Dawson, Ted M (2014) Motor neuron death in ALS: programmed by astrocytes? Neuron 81:961-3
Lasagna-Reeves, Cristian A; Sengupta, Urmi; Castillo-Carranza, Diana et al. (2014) The formation of tau pore-like structures is prevalent and cell specific: possible implications for the disease phenotypes. Acta Neuropathol Commun 2:56

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