Mice Deficient in TNF Receptors Are Protected Against Dopaminergic Neurotoxicity: Implications for Parkinson’s Disease

Details

• Personal Author:
  Benkovic SA ; Luster MI ; Matheson JM ; Miller DB ; O'Callaghan P ; Sriram K
• Description:
  The pathogenic mechanisms underlying idiopathic Parkinson's disease (PD) remain enigmatic. Recent findings suggest that inflammatory processes are associated with several neurodegenerative disorders, including PD. Enhanced expression of the proinflammatory cytokine, tumor necrosis factor (TNF)-alpha, has been found in association with glial cells in the substantia nigra of patients with PD. To determine the potential role for TNF-alpha in PD, we examined the effects of the 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP), a dopaminergic neurotoxin that mimics some of the key features associated with PD, using transgenic mice lacking TNF receptors. Administration of MPTP to wild-type (+/+) mice resulted in a time-dependent expression of TNF-alpha in striatum, which preceded the loss of dopaminergic markers and reactive gliosis. In contrast, transgenic mice carrying homozygous mutant alleles for both the TNF receptors (TNFR-DKO), but not the individual receptors, were completely protected against the dopaminergic neurotoxicity of MPTP. The data indicate that the proinflammatory cytokine TNF-alpha is an obligatory component of dopaminergic neurodegeneration. Moreover, because TNF-alpha is synthesized predominantly by microglia and astrocytes, our findings implicate the participation of glial cells in MPTP-induced neurotoxicity. Similar mechanisms may underlie the etiopathogenesis of PD. [Description provided by NIOSH]
• Subjects:
  Animals Laboratories Neoplasms Nervous System Occupational Health Safety
• Keywords:
  Animal-studies Author Keywords: Brain Laboratory-animals MPTP Neurodegeneration Neuromotor-function Neuromuscular-function Neuroprotection Neurotoxic-effects Neurotoxicity Neurotoxins Tumors

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• ISSN:
  0892-6638
• Document Type:
  Text
• Genre:
  Journal Article
• 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:
  16
• Issue:
  11
• NIOSHTIC Number:
  nn:20023020
• Citation:
  FASEB J 2002 Sep; 16(11):1474-1476
• Contact Point Address:
  James P. O'Callaghan, HELD/TMBB, CDC-NIOSH, Mailstop L-3014, 1095 Willowdale Road, Morgantown, WV 26505, USA
• Email:
  jdo5@cdc.gov
• CAS Registry Number:
  1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (CAS RN 28289-54-5)
• Federal Fiscal Year:
  2002
• Peer Reviewed:
  True
• Source Full Name:
  The FASEB Journal
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:401de80a93f1dec9893347a2372cf48bc3f8d5973129ee3cdf9ea54de2ed6ccb7231af9c84fed8e1d0b9953e5d946698c0c302782cab09c332588643d02c4aea
• Download URL:
  https://stacks.cdc.gov/view/cdc/199610/cdc_199610_DS1.pdf
• File Type:
  [PDF - 640.28 KB ]