PMID- 10770933
OWN - NLM
STAT- MEDLINE
DCOM- 20000810
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 275
IP  - 26
DP  - 2000 Jun 30
TI  - Embryonic striatal neurons from niemann-pick type C mice exhibit defects in 
      cholesterol metabolism and neurotrophin responsiveness.
PG  - 20179-87
AB  - Niemann-Pick type C (NP-C) disease is a progressive and fatal neuropathological 
      disorder previously characterized by abnormal cholesterol metabolism in 
      peripheral tissues. Although a defective gene has been identified in both humans 
      and the npc(nih) mouse model of NP-C disease, how this leads to abnormal neuronal 
      function is unclear. Here we show that whereas embryonic striatal neurons from 
      npc(nih) mice can take up low density lipoprotein-derived cholesterol, its 
      subsequent hydrolysis and esterification are significantly reduced. Given the 
      importance of cholesterol to a variety of signal transduction mechanisms, we 
      assessed the effect of this abnormality on the ability of these neurons to 
      respond to brain-derived neurotrophic factor (BDNF). In contrast to its effects 
      on wild type neurons, BDNF failed to induce autophosphorylation of the TrkB 
      receptor and to increase neurite outgrowth in npc(nih) neurons, despite 
      expression of TrkB on the cell surface. The results suggest that abnormal 
      cholesterol metabolism occurs in neurons in the brain during NP-C disease, even 
      at embryonic stages of development prior to the onset of phenotypic symptoms. 
      Moreover, this defect is associated with a lack of TrkB function and BDNF 
      responsiveness, which may contribute to the loss of neuronal function observed in 
      NP-C disease.
FAU - Henderson, L P
AU  - Henderson LP
AD  - Departments of Physiology and Biochemistry, Dartmouth Medical School, Hanover, 
      New Hampshire 03755, USA.
FAU - Lin, L
AU  - Lin L
FAU - Prasad, A
AU  - Prasad A
FAU - Paul, C A
AU  - Paul CA
FAU - Chang, T Y
AU  - Chang TY
FAU - Maue, R A
AU  - Maue RA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Cholesterol, LDL)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Lipids)
RN  - 0 (Nerve Growth Factors)
RN  - 0 (Niemann-Pick C1 Protein)
RN  - 0 (Npc1 protein, mouse)
RN  - 0 (Proteins)
RN  - 0 (Sphingolipids)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 4.1.1.15 (Glutamate Decarboxylase)
SB  - IM
MH  - Animals
MH  - Biotinylation
MH  - Blotting, Western
MH  - Brain-Derived Neurotrophic Factor/pharmacology
MH  - Cells, Cultured
MH  - Cholesterol/*metabolism/pharmacokinetics
MH  - Cholesterol, LDL/pharmacokinetics
MH  - Corpus Striatum/embryology/*metabolism
MH  - Disease Models, Animal
MH  - Genotype
MH  - Glutamate Decarboxylase/metabolism
MH  - Immunohistochemistry
MH  - Intracellular Signaling Peptides and Proteins
MH  - Membrane Lipids/metabolism
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Mutation
MH  - Nerve Growth Factors/*metabolism
MH  - Neurons/metabolism
MH  - Niemann-Pick C1 Protein
MH  - Niemann-Pick Diseases/*genetics/metabolism
MH  - Proteins/*genetics
MH  - Receptor, trkB/metabolism
MH  - Signal Transduction
MH  - Sphingolipids/metabolism/pharmacokinetics
EDAT- 2000/04/20 09:00
MHDA- 2000/08/12 11:00
CRDT- 2000/04/20 09:00
PHST- 2000/04/20 09:00 [pubmed]
PHST- 2000/08/12 11:00 [medline]
PHST- 2000/04/20 09:00 [entrez]
AID - S0021-9258(19)80101-1 [pii]
AID - 10.1074/jbc.M001793200 [doi]
PST - ppublish
SO  - J Biol Chem. 2000 Jun 30;275(26):20179-87. doi: 10.1074/jbc.M001793200.