Glial Signaling, TNF-Alpha and Dopaminergic Neurodegeneration

Details

• Personal Author:
  O'Callaghan JP ; Sriram K
• Description:
  The pathogenic mechanisms underlying Parkinson's disease (PD) remain enigmatic. To identify early molecular events associated with PD, we profiled genomic and proteomic changes in the MPTP mouse model of PD. Specifically, we focused on the role of TNF-a, IL-1B and IL-6, since enhanced expression of these proinflammatory cytokines has been found in association with glial cells of patients with PD. MPTP caused a time-dependent increase in the mRNA expression of these cytokines in striatum, but not in hippocampus, and their expression preceded striatal dopaminergic degeneration (loss of dopamine and tyrosine hydroxylase), activation of JAK/STAT3 pathway and astrogliosis (upregulation of GFAP). Deficiency of the IL-6 gene did not alter striatal nerve terminal loss, but attenuated astrogliosis. However, in transgenic mice lacking TNF receptors (TNFR-DKO), loss of striatal dopaminergic markers, phosphorylation of STAT3, upregulation of GFAP and astrocyte hypertrophy were nearly abolished. Interestingly, the lack of TNF receptors exacerbated hippocampal neuronal damage (increased Fluoro Jade-B staining and loss of MAP-2 immunoreactivity) after MPTP. These findings implicate a region specific role for TNF-a in the brain: a promoter of neurodegeneration in striatum and a protector against neurodegeneration in hippocampus. From a Parkinson's disease perspective, these findings are suggestive of a primary role for TNF-a in the pathogenesis of this disorder. As deficiency of TNF receptors attenuated phosphorylation of JAK-STAT3 and upregulation of GFAP, the findings implicate these signaling pathways in upregulation of GFAP. Since the activation of these pathways are early events in MPTP neurotoxicity, they may serve as potential therapeutic targets for modulation of neuronal loss and/or glial response following dopaminergic neurodegeneration. [Description provided by NIOSH]
• Subjects:
  Animals Laboratories Nervous System Nervous System Diseases Nervous System Disorders Occupational Health Safety
• Keywords:
  Animal-studies Central-nervous-system Central-nervous-system-disorders Laboratory-animals Neuromuscular-system-disorders
• ISSN:
  0022-3042
• Document Type:
  Text
• Genre:
  Abstract or Summary ; Proceedings
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  94
• NIOSHTIC Number:
  nn:20028933
• Citation:
  J Neurochem 2005 Aug; 94(Suppl 2):130
• Federal Fiscal Year:
  2005
• Peer Reviewed:
  False
• Source Full Name:
  Journal of Neurochemistry
• Supplement:
  2
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:1c83d3a4fd79f217f8ca208e25a2a5b781db3b343dc2251c47744f28d1dabbcf006809e96b6c8a85c7365c1ccb832c1fdcf33346f8111c3194b93c6350450c57
• Download URL:
  https://stacks.cdc.gov/view/cdc/190021/cdc_190021_DS1.pdf
• File Type:
  [PDF - 47.26 KB ]