PMID- 22932872
OWN - NLM
STAT- MEDLINE
DCOM- 20121210
LR  - 20220419
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 109
IP  - 37
DP  - 2012 Sep 11
TI  - Autophagy activators rescue and alleviate pathogenesis of a mouse model with 
      proteinopathies of the TAR DNA-binding protein 43.
PG  - 15024-9
LID - 10.1073/pnas.1206362109 [doi]
AB  - TDP-43 is a multifunctional DNA/RNA-binding protein that has been identified as 
      the major component of the cytoplasmic ubiquitin (+) inclusions (UBIs) in 
      diseased cells of frontotemporal lobar dementia (FTLD-U) and amyotrophic lateral 
      sclerosis (ALS). Unfortunately, effective drugs for these neurodegenerative 
      diseases are yet to be developed. We have tested the therapeutic potential of 
      rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) and three 
      other autophagy activators (spermidine, carbamazepine, and tamoxifen) in a FTLD-U 
      mouse model with TDP-43 proteinopathies. Rapamycin treatment has been reported to 
      be beneficial in some animal models of neurodegenerative diseases but not others. 
      Furthermore, the effects of rapamycin treatment in FTLD-U have not been 
      investigated. We show that rapamycin treatment effectively rescues the 
      learning/memory impairment of these mice at 3 mo of age, and it significantly 
      slows down the age-dependent loss of their motor function. These behavioral 
      improvements upon rapamycin treatment are accompanied by a decreased level of 
      caspase-3 and a reduction of neuron loss in the forebrain of FTLD-U mice. 
      Furthermore, the number of cells with cytosolic TDP-43 (+) inclusions and the 
      amounts of full-length TDP-43 as well as its cleavage products (35 kDa and 25 
      kDa) in the urea-soluble fraction of the cellular extract are significantly 
      decreased upon rapamycin treatment. These changes in TDP-43 metabolism are 
      accompanied by rapamycin-induced decreases in mTOR-regulated phospho-p70 S6 
      kinase (P-p70) and the p62 protein, as well as increases in the autophagic marker 
      LC3. Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could 
      also rescue the motor dysfunction of 7-mo-old FTLD-U mice. These data suggest 
      that autophagy activation is a potentially useful route for the therapy of 
      neurodegenerative diseases with TDP-43 proteinopathies.
FAU - Wang, I-Fang
AU  - Wang IF
AD  - Institute of Life Science, National Defense Medical Center, Taipei, Taiwan 11490.
FAU - Guo, Bo-Shen
AU  - Guo BS
FAU - Liu, Yu-Chih
AU  - Liu YC
FAU - Wu, Cheng-Chun
AU  - Wu CC
FAU - Yang, Chun-Hung
AU  - Yang CH
FAU - Tsai, Kuen-Jer
AU  - Tsai KJ
FAU - Shen, Che-Kun James
AU  - Shen CK
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120829
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  - 094ZI81Y45 (Tamoxifen)
RN  - 33CM23913M (Carbamazepine)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.22.- (Caspase 3)
RN  - U87FK77H25 (Spermidine)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Autophagy/*drug effects
MH  - Blotting, Western
MH  - Carbamazepine/pharmacology
MH  - Caspase 3/metabolism
MH  - Fluorometry
MH  - Frontotemporal Dementia/*complications/*drug therapy/physiopathology
MH  - In Situ Nick-End Labeling
MH  - Maze Learning/drug effects
MH  - Memory Disorders/drug therapy
MH  - Mice
MH  - Psychomotor Performance/drug effects
MH  - Rotarod Performance Test
MH  - Sirolimus/*pharmacology/therapeutic use
MH  - Spermidine/pharmacology
MH  - TDP-43 Proteinopathies/*complications/*drug therapy/physiopathology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
MH  - Tamoxifen/pharmacology
PMC - PMC3443184
COIS- The authors declare no conflict of interest.
EDAT- 2012/08/31 06:00
MHDA- 2012/12/12 06:00
PMCR- 2013/03/11
CRDT- 2012/08/31 06:00
PHST- 2012/08/31 06:00 [entrez]
PHST- 2012/08/31 06:00 [pubmed]
PHST- 2012/12/12 06:00 [medline]
PHST- 2013/03/11 00:00 [pmc-release]
AID - 1206362109 [pii]
AID - 201206362 [pii]
AID - 10.1073/pnas.1206362109 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):15024-9. doi: 
      10.1073/pnas.1206362109. Epub 2012 Aug 29.