Molecular Mechanisms of Lrrk2-Associated Neurodegeneration in Parkinson's Disease.
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Molecular Mechanisms of Lrrk2-Associated Neurodegeneration in Parkinson's Disease.

Molecular Mechanisms of Lrrk2-Associated Neurodegeneration in Parkinson's Disease.


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About the Book

Neurodegenerative illnesses such as Parkinson and Alzheimer disease are an increasingly prevalent problem in aging societies, yet no therapies exist that retard or prevent neurodegeneration. Dominant missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD) and have also been associated with dementia. However, the mechanisms by which mutant forms of LRRK2 disrupt neuronal function and cause cell death remain poorly understood. We report that LRRK2 interacts with the death adaptor protein FADD, and that in primary neuronal culture LRRK2-mediated neurodegeneration is prevented by the functional inhibition of FADD or depletion of caspase-8, two key elements of the extrinsic cell death pathway. This pathway is activated by disease-triggering mutations, which enhance the LRRK2-FADD association and the consequent recruitment and activation of caspase-8. These results establish a direct molecular link between a mutant PD gene and the activation of programmed cell death signaling. We also demonstrated that multiple LRRK2 mutations abnormally enhance LRRK2 oligomerization through a kinase-dependent mechanism. In contrast, the one PD mutation that does not enhance LRRK2 oligomerization is also the only one that markedly enhances its kinase activity. Our observations link LRRK2 oligomerization to its interaction with FADD/caspase-8, and suggest that agents reducing LRRK2 oligomerization or formation of death signaling complex may represent a new therapeutic strategy to block LRRK2-dependent neurodegeneration.


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Product Details
  • ISBN-13: 9781243582942
  • Publisher: Proquest, Umi Dissertation Publishing
  • Publisher Imprint: Proquest, Umi Dissertation Publishing
  • Height: 246 mm
  • Weight: 177 gr
  • ISBN-10: 1243582944
  • Publisher Date: 01 Sep 2011
  • Binding: Paperback
  • Spine Width: 5 mm
  • Width: 189 mm


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Molecular Mechanisms of Lrrk2-Associated Neurodegeneration in Parkinson's Disease.
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Molecular Mechanisms of Lrrk2-Associated Neurodegeneration in Parkinson's Disease.
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