PMID- 20826683
OWN - NLM
STAT- MEDLINE
DCOM- 20101004
LR  - 20220311
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 30
IP  - 36
DP  - 2010 Sep 8
TI  - Tumor necrosis factor-alpha (TNF-alpha) regulates shedding of TNF-alpha receptor 
      1 by the metalloprotease-disintegrin ADAM8: evidence for a protease-regulated 
      feedback loop in neuroprotection.
PG  - 12210-8
LID - 10.1523/JNEUROSCI.1520-10.2010 [doi]
AB  - Tumor necrosis factor alpha (TNF-alpha) is a potent cytokine in neurodegenerative 
      disorders, but its precise role in particular brain disorders is ambiguous. In 
      motor neuron (MN) disease of the mouse, exemplified by the model wobbler (WR), 
      TNF-alpha causes upregulation of the metalloprotease-disintegrin ADAM8 (A8) in 
      affected brain regions, spinal cord, and brainstem. The functional role of A8 
      during MN degeneration in the wobbler CNS was investigated by crossing WR with 
      A8-deficient mice: a severely aggravated neuropathology was observed for 
      A8-deficient WR compared with WR A8(+/-) mice, judged by drastically reduced 
      survival [7 vs 81% survival at postnatal day 50 (P50)], accelerated force loss in 
      the forelimbs, and terminal akinesis. In vitro protease assays using soluble A8 
      indicated specific cleavage of a TNF-alpha receptor 1 (p55 TNF-R1) but not a 
      TNF-R2 peptide. Cleavage of TNF-R1 was confirmed in situ, because levels of 
      soluble TNF-R1 were increased in spinal cords of standard WR compared with 
      wild-type mice but not in A8-deficient WR mice. In isolated primary neurons and 
      microglia, TNF-alpha-induced TNF-R1 shedding was dependent on the A8 gene dosage. 
      Furthermore, exogenous TNF-alpha showed higher toxicity for cultured neurons from 
      A8-deficient than for those from wild-type mice, demonstrating that TNF-R1 
      shedding by A8 is neuroprotective. Our results indicate an essential role for 
      ADAM8 in modulating TNF-alpha signaling in CNS diseases: a feedback loop 
      integrating TNF-alpha, ADAM8, and TNF-R1 shedding as a plausible mechanism for 
      TNF-alpha mediated neuroprotection in situ and a rationale for therapeutic 
      intervention.
FAU - Bartsch, Jorg W
AU  - Bartsch JW
AD  - Pharmaceutical Science Research Division, King's College London, London, United 
      Kingdom. jorg.bartsch@kcl.ac.uk
FAU - Wildeboer, Dirk
AU  - Wildeboer D
FAU - Koller, Garrit
AU  - Koller G
FAU - Naus, Silvia
AU  - Naus S
FAU - Rittger, Andrea
AU  - Rittger A
FAU - Moss, Marcia L
AU  - Moss ML
FAU - Minai, Yuji
AU  - Minai Y
FAU - Jockusch, Harald
AU  - Jockusch H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Antigens, CD)
RN  - 0 (Membrane Proteins)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type I)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type II)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.1.3.48 (Leukocyte Common Antigens)
RN  - EC 3.1.3.48 (Ptprc protein, mouse)
RN  - EC 3.4.24.- (ADAM Proteins)
RN  - EC 3.4.24.- (Adam8 protein, mouse)
SB  - IM
MH  - ADAM Proteins/deficiency/genetics/*metabolism/pharmacology
MH  - Animals
MH  - Animals, Newborn
MH  - Antigens, CD/genetics/*metabolism/pharmacology
MH  - Cell Count/methods
MH  - Central Nervous System/metabolism/pathology
MH  - Dose-Response Relationship, Drug
MH  - Enzyme-Linked Immunosorbent Assay/methods
MH  - Gene Expression Regulation/*genetics
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Leukocyte Common Antigens/metabolism
MH  - Membrane Proteins/deficiency/genetics/*metabolism/pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Muscular Atrophy/genetics
MH  - Nerve Tissue Proteins/metabolism
MH  - Neurodegenerative Diseases/*genetics/mortality/pathology
MH  - Neuroglia/drug effects/metabolism
MH  - Neurons/drug effects/metabolism
MH  - RNA, Messenger/metabolism
MH  - Receptors, Tumor Necrosis Factor, Type I/drug effects/*metabolism
MH  - Receptors, Tumor Necrosis Factor, Type II/metabolism
MH  - Tumor Necrosis Factor-alpha/*metabolism/pharmacology
PMC - PMC6633558
EDAT- 2010/09/10 06:00
MHDA- 2010/10/05 06:00
PMCR- 2011/03/08
CRDT- 2010/09/10 06:00
PHST- 2010/09/10 06:00 [entrez]
PHST- 2010/09/10 06:00 [pubmed]
PHST- 2010/10/05 06:00 [medline]
PHST- 2011/03/08 00:00 [pmc-release]
AID - 30/36/12210 [pii]
AID - 3630996 [pii]
AID - 10.1523/JNEUROSCI.1520-10.2010 [doi]
PST - ppublish
SO  - J Neurosci. 2010 Sep 8;30(36):12210-8. doi: 10.1523/JNEUROSCI.1520-10.2010.