Reactive Microgliosis and Progressive Dopaminergic Neurotoxicity

Project: Research project

Description

Parkinson's disease (PD) is a devastating movement disorder characterized by the progressive loss of
dopaminergic (DA) neurons in the substantia nigra, where mechanisms of DA neuron loss are poorly
understood. While PD affects approximately 1.5% of the North American population, available treatments
only temporarily ameliorate PD symptoms and can not slow disease progression. The majority of PD cases
are sporadic and environmental toxicants are linked to PD etiology. Microglia, the resident macrophage in
the brain, are believed to contribute to the progressive nature of PD. Microglia are activated upon DA
neuron injury to result in inflammation and damage to neighboring DA neurons (reactive microgliosis), but
the mechanisms responsible are largely unknown. Here, we address the over-arching hypothesis that
soluble neuron-injury factors are released upon environmental insult (MPP+/MPTP) to promote microglial
activation, which drives further DA neurotoxicity, to result in a vicious, self-propelling cycle. This study is
focused on u calpain, an intracellular calcium-dependant protease that is reported to be released
extracellularly upon cortical neuron damage. Using a combined in vitro/in vivo approach, we will test the
specific hypothesis that u calpain is a key soluble factor released upon DA neuron damage with
MPP+/MPTP to activate microglia, which then potentiates additional DA neurotoxicity. The specific aims of
this proposal are to: 1) determine the pro-inflammatory and neurotoxic characteristics of soluble factors
released from DA neurons exposed to the direct neurotoxicant MPP+ (Mentored Phase); 2) characterize u
calpain as a soluble neuron-injury factor contributing to reactive microgliosis (Independent Phase); 3)
characterize the MAC1 receptor-mediated mechanism of u calpain-induced microglia activation and DA
neurotoxicity (Independent Phase); 4) define the enhancing action of u calpain on progressive
neurodegeneration, both in vitro and in an in vivo MPTP mouse model (Independent Phase). The proposed
studies will reveal novel molecular signals that drive self-propelling neurodegeneration and identify
therapeutic targets with the potential to slow PD progression. Additionally, this research will establish the
groundwork for further studies into the mechanisms by which environmental factors contribute to reactive
microgliosis, progressive neurotoxicity, and PD.
StatusFinished
Effective start/end date3/1/0812/31/10

Funding

  • National Institutes of Health: $244,414.00
  • National Institutes of Health: $242,560.00
  • National Institutes of Health: $240,574.00

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Parkinson Disease
Neurons
Calpain
Microglia
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Disease Progression
Wounds and Injuries
Movement Disorders
Substantia Nigra
Peptide Hydrolases
Macrophages
Inflammation
Calcium
Brain
Research
Population