PMID- 11408619
OWN - NLM
STAT- MEDLINE
DCOM- 20010726
LR  - 20220321
IS  - 0036-8075 (Print)
IS  - 0036-8075 (Linking)
VI  - 293
IP  - 5529
DP  - 2001 Jul 20
TI  - Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease.
PG  - 493-8
AB  - Huntingtin is a 350-kilodalton protein of unknown function that is mutated in 
      Huntington's disease (HD), a neurodegenerative disorder. The mutant protein is 
      presumed to acquire a toxic gain of function that is detrimental to striatal 
      neurons in the brain. However, loss of a beneficial activity of wild-type 
      huntingtin may also cause the death of striatal neurons. Here we demonstrate that 
      wild-type huntingtin up-regulates transcription of brain-derived neurotrophic 
      factor (BDNF), a pro-survival factor produced by cortical neurons that is 
      necessary for survival of striatal neurons in the brain. We show that this 
      beneficial activity of huntingtin is lost when the protein becomes mutated, 
      resulting in decreased production of cortical BDNF. This leads to insufficient 
      neurotrophic support for striatal neurons, which then die. Restoring wild-type 
      huntingtin activity and increasing BDNF production may be therapeutic approaches 
      for treating HD.
FAU - Zuccato, C
AU  - Zuccato C
AD  - Department of Pharmacological Sciences, University of Milano, Via Balzaretti 9, 
      20133 Milano, Italy.
FAU - Ciammola, A
AU  - Ciammola A
FAU - Rigamonti, D
AU  - Rigamonti D
FAU - Leavitt, B R
AU  - Leavitt BR
FAU - Goffredo, D
AU  - Goffredo D
FAU - Conti, L
AU  - Conti L
FAU - MacDonald, M E
AU  - MacDonald ME
FAU - Friedlander, R M
AU  - Friedlander RM
FAU - Silani, V
AU  - Silani V
FAU - Hayden, M R
AU  - Hayden MR
FAU - Timmusk, T
AU  - Timmusk T
FAU - Sipione, S
AU  - Sipione S
FAU - Cattaneo, E
AU  - Cattaneo E
LA  - eng
GR  - E.0840/TI_/Telethon/Italy
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20010614
PL  - United States
TA  - Science
JT  - Science (New York, N.Y.)
JID - 0404511
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (HTT protein, human)
RN  - 0 (Htt protein, mouse)
RN  - 0 (Huntingtin Protein)
RN  - 0 (Nerve Growth Factors)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nuclear Proteins)
SB  - IM
CIN - Science. 2001 Jul 20;293(5529):445-6. PMID: 11463904
MH  - 3T3 Cells
MH  - Animals
MH  - Apoptosis
MH  - Brain-Derived Neurotrophic Factor/biosynthesis/*genetics/metabolism
MH  - Cell Survival
MH  - Cells, Cultured
MH  - Cerebral Cortex/cytology/*metabolism
MH  - Corpus Striatum/cytology/*metabolism/pathology
MH  - Exons
MH  - Hippocampus/cytology/metabolism/pathology
MH  - Humans
MH  - Huntingtin Protein
MH  - Huntington Disease/*genetics/metabolism/pathology
MH  - Mice
MH  - Mice, Transgenic
MH  - Mutation
MH  - Nerve Degeneration
MH  - Nerve Growth Factors/genetics/metabolism
MH  - Nerve Tissue Proteins/genetics/*physiology
MH  - Neurons/*metabolism/pathology
MH  - Nuclear Proteins/genetics/*physiology
MH  - Promoter Regions, Genetic
MH  - Transcription, Genetic
MH  - Transfection
EDAT- 2001/06/16 10:00
MHDA- 2001/07/28 10:01
CRDT- 2001/06/16 10:00
PHST- 2001/06/16 10:00 [pubmed]
PHST- 2001/07/28 10:01 [medline]
PHST- 2001/06/16 10:00 [entrez]
AID - 1059581 [pii]
AID - 10.1126/science.1059581 [doi]
PST - ppublish
SO  - Science. 2001 Jul 20;293(5529):493-8. doi: 10.1126/science.1059581. Epub 2001 Jun 
      14.