Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by resting tremor, rigidity and bradykinesia. These clinical features are thought to arise from reduced dopaminergic input to the striatum, which is caused by the degeneration of dopaminergic neurons in the substantia nigra. The occurrence of PD is largely sporadic, but clinical syndromes resembling sporadic PD have been linked to mutations in at least 5 distinct genes (1-synuclein, parkin, DJ-1, PINK1 and LRRK2). Elucidation of the pathogenic mechanisms underlying the selective dopaminergic degeneration in familial parkinsonism will likely provide important clues to the pathogenic mechanisms responsible for idiopathic PD. The recessive inheritance mode of the mutations and the existence of large deletions in the parkin, DJ-1 and PINK1 genes indicate a loss-of-function pathogenic mechanism. Our previous generation and multidisciplinary analysis of parkin-/-, DJ-1-/- and PINK1-/- mice have demonstrated that each of these gene products is required for normal dopaminergic function and evoked dopamine (DA) release in nigrostriatal terminals. Our recent work showed that LRRK2 R1441C knockin (KI) mice exhibit similar defects in dopaminergic neurotransmission and DA release. Thus, presynaptic dopaminergic dysfunction may be a central converging pathogenic mechanism for PD. Our studies also showed that loss of PINK1 or Parkin impairs mitochondrial function, suggesting that impairment of mitochondrial respiration in the absence of PINK1 or Parkin may underlie the DA release defect. In this competing renewal application, we propose two Specific Aims to continue our investigation of PD pathogenic mechanisms. First, we will elucidate the mechanism underlying mitochondrial respiration defects caused by loss of PINK1 or Parkin, and determine whether mitochondrial calcium homeostasis and cell death susceptibility are affected. Second, we will further explore dopamine neurotransmission in vivo and determine whether the defect in evoked DA release is caused by disrupted calcium homeostasis and whether loss of PINK1 or Parkin renders cells more sensitive to mitochondrial inhibition. The completion of the proposed study will provide significant insight into the biology of PINK1 and Parkin as well as their regulation of DA release, and will determine whether disruption of calcium homeostasis is a key unifying event in DA neurotransmission, mitochondrial function and cell death susceptibility. Our long-term goal is to understand the pathogenic mechanism underlying dopaminergic dysfunction and degeneration, and to characterize the cellular and molecular pathways responsible for PD pathogenesis.

Public Health Relevance

Parkinson's disease (PD) is the most common movement disorder, and mutations in at least 5 distinct genes are responsible for inherited forms of the disease. In this application, we propose to study how loss of PINK1 or Parkin causes dopaminergic dysfunction and degeneration. Completion of our proposed study will provide insights into PD pathogenesis and may identify novel therapeutic targets for development of more effective drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041779-13
Application #
8462694
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Sutherland, Margaret L
Project Start
2001-05-15
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
13
Fiscal Year
2013
Total Cost
$360,497
Indirect Cost
$153,625
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Madeo, Graziella; Schirinzi, Tommaso; Martella, Giuseppina et al. (2014) PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity. Mov Disord 29:41-53
Lee, Sang Hun; Sharma, Manu; S├╝dhof, Thomas C et al. (2014) Synaptic function of nicastrin in hippocampal neurons. Proc Natl Acad Sci U S A 111:8973-8
Wu, Bei; Yamaguchi, Hiroo; Lai, F Anthony et al. (2013) Presenilins regulate calcium homeostasis and presynaptic function via ryanodine receptors in hippocampal neurons. Proc Natl Acad Sci U S A 110:15091-6
Yamaguchi, Hiroo; Shen, Jie (2013) Histological analysis of neurodegeneration in the mouse brain. Methods Mol Biol 1004:91-113
Madeo, G; Martella, G; Schirinzi, T et al. (2012) Aberrant striatal synaptic plasticity in monogenic parkinsonisms. Neuroscience 211:126-35
Tong, Youren; Giaime, Emilie; Yamaguchi, Hiroo et al. (2012) Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway. Mol Neurodegener 7:2
Martella, G; Madeo, G; Schirinzi, T et al. (2011) Altered profile and D2-dopamine receptor modulation of high voltage-activated calcium current in striatal medium spiny neurons from animal models of Parkinson's disease. Neuroscience 177:240-51
Narendra, Derek P; Jin, Seok Min; Tanaka, Atsushi et al. (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8:e1000298
Kitada, Tohru; Tong, Youren; Gautier, Clement A et al. (2009) Absence of nigral degeneration in aged parkin/DJ-1/PINK1 triple knockout mice. J Neurochem 111:696-702
Tong, Youren; Shen, Jie (2009) alpha-synuclein and LRRK2: partners in crime. Neuron 64:771-3

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