PMID- 32393629
OWN - NLM
STAT- MEDLINE
DCOM- 20200818
LR  - 20240328
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 117
IP  - 21
DP  - 2020 May 26
TI  - TDP-43 dysfunction restricts dendritic complexity by inhibiting CREB activation 
      and altering gene expression.
PG  - 11760-11769
LID - 10.1073/pnas.1917038117 [doi]
AB  - Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two 
      related neurodegenerative diseases that present with similar TDP-43 pathology in 
      patient tissue. TDP-43 is an RNA-binding protein which forms aggregates in 
      neurons of ALS and FTD patients as well as in a subset of patients diagnosed with 
      other neurodegenerative diseases. Despite our understanding that TDP-43 is 
      essential for many aspects of RNA metabolism, it remains obscure how TDP-43 
      dysfunction contributes to neurodegeneration. Interestingly, altered neuronal 
      dendritic morphology is a common theme among several neurological disorders and 
      is thought to precede neurodegeneration. We previously found that both TDP-43 
      overexpression (OE) and knockdown (KD) result in reduced dendritic branching of 
      cortical neurons. In this study, we used TRIBE (targets of RNA-binding proteins 
      identified by editing) as an approach to identify signaling pathways that 
      regulate dendritic branching downstream of TDP-43. We found that TDP-43 RNA 
      targets are enriched for pathways that signal to the CREB transcription factor. 
      We further found that TDP-43 dysfunction inhibits CREB activation and CREB 
      transcriptional output, and restoring CREB signaling rescues defects in dendritic 
      branching. Finally, we demonstrate, using RNA sequencing, that TDP-43 OE and KD 
      cause similar changes in the abundance of specific messenger RNAs, consistent 
      with their ability to produce similar morphological defects. Our data therefore 
      provide a mechanism by which TDP-43 dysfunction interferes with dendritic 
      branching, and may define pathways for therapeutic intervention in 
      neurodegenerative diseases.
FAU - Herzog, Josiah J
AU  - Herzog JJ
AD  - Department of Biology, Brandeis University, Waltham, MA 02453.
AD  - Volen Center for Complex Systems, Brandeis University, Waltham, MA 02453.
FAU - Xu, Weijin
AU  - Xu W
AUID- ORCID: 0000-0003-1634-5241
AD  - Department of Biology, Brandeis University, Waltham, MA 02453.
AD  - Howard Hughes Medical Institute, Brandeis University, Waltham, MA 02453.
FAU - Deshpande, Mugdha
AU  - Deshpande M
AD  - Department of Biology, Brandeis University, Waltham, MA 02453.
AD  - Volen Center for Complex Systems, Brandeis University, Waltham, MA 02453.
FAU - Rahman, Reazur
AU  - Rahman R
AD  - Department of Biology, Brandeis University, Waltham, MA 02453.
AD  - Howard Hughes Medical Institute, Brandeis University, Waltham, MA 02453.
FAU - Suib, Hannah
AU  - Suib H
AD  - Department of Biology, Brandeis University, Waltham, MA 02453.
AD  - Volen Center for Complex Systems, Brandeis University, Waltham, MA 02453.
FAU - Rodal, Avital A
AU  - Rodal AA
AUID- ORCID: 0000-0002-2051-8304
AD  - Department of Biology, Brandeis University, Waltham, MA 02453.
FAU - Rosbash, Michael
AU  - Rosbash M
AD  - Department of Biology, Brandeis University, Waltham, MA 02453; 
      rosbash@brandeis.edu paradis@brandeis.edu.
AD  - Howard Hughes Medical Institute, Brandeis University, Waltham, MA 02453.
FAU - Paradis, Suzanne
AU  - Paradis S
AD  - Department of Biology, Brandeis University, Waltham, MA 02453; 
      rosbash@brandeis.edu paradis@brandeis.edu.
AD  - Volen Center for Complex Systems, Brandeis University, Waltham, MA 02453.
LA  - eng
GR  - R01 NS065856/NS/NINDS NIH HHS/United States
GR  - R56 NS065856/NS/NINDS NIH HHS/United States
GR  - R01 NS103967/NS/NINDS NIH HHS/United States
GR  - R01 DA037721/DA/NIDA NIH HHS/United States
GR  - R01 AG052465/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200511
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (CREB1 protein, human)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (TARDBP protein, human)
SB  - IM
MH  - Animals
MH  - *Cyclic AMP Response Element-Binding Protein/genetics/metabolism
MH  - *DNA-Binding Proteins/genetics/metabolism
MH  - *Dendrites/metabolism/pathology
MH  - Gene Expression Regulation/*genetics
MH  - HEK293 Cells
MH  - Humans
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - *Signal Transduction/genetics/physiology
MH  - TDP-43 Proteinopathies
PMC - PMC7260973
OTO - NOTNLM
OT  - CREB
OT  - TDP-43
OT  - TRIBE
COIS- Competing interest statement: W.X. and M.R. declare that a PCT patent application 
      (PCT patent application no. PCT/US2016/054525) has been filed on the TRIBE 
      technique.
EDAT- 2020/05/13 06:00
MHDA- 2020/08/19 06:00
PMCR- 2020/11/11
CRDT- 2020/05/13 06:00
PHST- 2020/05/13 06:00 [pubmed]
PHST- 2020/08/19 06:00 [medline]
PHST- 2020/05/13 06:00 [entrez]
PHST- 2020/11/11 00:00 [pmc-release]
AID - 1917038117 [pii]
AID - 201917038 [pii]
AID - 10.1073/pnas.1917038117 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2020 May 26;117(21):11760-11769. doi: 
      10.1073/pnas.1917038117. Epub 2020 May 11.