PMID- 24048383
OWN - NLM
STAT- MEDLINE
DCOM- 20140421
LR  - 20220316
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 4
DP  - 2013
TI  - Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal 
      growth cone retraction.
PG  - 2490
LID - 10.1038/ncomms3490 [doi]
AB  - A common single-nucleotide polymorphism (SNP) in the human brain-derived 
      neurotrophic factor (BDNF) gene results in a Val66Met substitution in the BDNF 
      prodomain region. This SNP is associated with alterations in memory and with 
      enhanced risk to develop depression and anxiety disorders in humans. Here we show 
      that the isolated BDNF prodomain is detected in the hippocampus and that it can 
      be secreted from neurons in an activity-dependent manner. Using nuclear magnetic 
      resonance spectroscopy and circular dichroism, we find that the prodomain is 
      intrinsically disordered, and the Val66Met substitution induces structural 
      changes. Surprisingly, application of Met66 (but not Val66) BDNF prodomain 
      induces acute growth cone retraction and a decrease in Rac activity in 
      hippocampal neurons. Expression of p75(NTR) and differential engagement of the 
      Met66 prodomain to the SorCS2 receptor are required for this effect. These 
      results identify the Met66 prodomain as a new active ligand, which modulates 
      neuronal morphology.
FAU - Anastasia, Agustin
AU  - Anastasia A
AD  - Department of Medicine, Weill Cornell Medical College of Cornell University, 1300 
      York Avenue, New York, New York 10065, USA.
FAU - Deinhardt, Katrin
AU  - Deinhardt K
FAU - Chao, Moses V
AU  - Chao MV
FAU - Will, Nathan E
AU  - Will NE
FAU - Irmady, Krithi
AU  - Irmady K
FAU - Lee, Francis S
AU  - Lee FS
FAU - Hempstead, Barbara L
AU  - Hempstead BL
FAU - Bracken, Clay
AU  - Bracken C
LA  - eng
GR  - S10-RR023694-01EWOF/RR/NCRR NIH HHS/United States
GR  - P01 HD023315/HD/NICHD NIH HHS/United States
GR  - R01 NS064114/NS/NINDS NIH HHS/United States
GR  - NS21072/NS/NINDS NIH HHS/United States
GR  - R01 NS021072/NS/NINDS NIH HHS/United States
GR  - S10 RR023694/RR/NCRR NIH HHS/United States
GR  - R01 NS052819/NS/NINDS NIH HHS/United States
GR  - HD23315/HD/NICHD NIH HHS/United States
GR  - R01 NS030687/NS/NINDS NIH HHS/United States
GR  - R01 AG025970/AG/NIA NIH HHS/United States
GR  - NS030687/NS/NINDS NIH HHS/United States
GR  - R56 NS021072/NS/NINDS NIH HHS/United States
GR  - NS064114/NS/NINDS NIH HHS/United States
GR  - NS052819/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (NGFR protein, human)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Receptors, Nerve Growth Factor)
RN  - 0 (Recombinant Proteins)
RN  - 0 (SORCS2 protein, human)
RN  - 7171WSG8A2 (BDNF protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
EIN - Nat Commun. 2014;5:3564
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*genetics/metabolism
MH  - Embryo, Mammalian
MH  - Escherichia coli/genetics
MH  - Gene Expression Regulation, Developmental
MH  - Growth Cones/*metabolism/pathology
MH  - HEK293 Cells
MH  - Hippocampus/growth & development/*metabolism/pathology
MH  - Humans
MH  - Magnetic Resonance Spectroscopy
MH  - Memory/physiology
MH  - Mice
MH  - Mice, Knockout
MH  - Nerve Tissue Proteins/genetics/metabolism
MH  - Neurogenesis/genetics
MH  - *Polymorphism, Single Nucleotide
MH  - Protein Structure, Secondary
MH  - Protein Structure, Tertiary
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - Rats
MH  - Receptors, Cell Surface/genetics/metabolism
MH  - Receptors, Nerve Growth Factor/genetics/metabolism
MH  - Recombinant Proteins/genetics/metabolism
PMC - PMC3820160
MID - NIHMS517924
EDAT- 2013/09/21 06:00
MHDA- 2014/04/22 06:00
PMCR- 2014/03/18
CRDT- 2013/09/20 06:00
PHST- 2013/04/18 00:00 [received]
PHST- 2013/08/21 00:00 [accepted]
PHST- 2013/09/20 06:00 [entrez]
PHST- 2013/09/21 06:00 [pubmed]
PHST- 2014/04/22 06:00 [medline]
PHST- 2014/03/18 00:00 [pmc-release]
AID - ncomms3490 [pii]
AID - 10.1038/ncomms3490 [doi]
PST - ppublish
SO  - Nat Commun. 2013;4:2490. doi: 10.1038/ncomms3490.