Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43

Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):15024-9. doi: 10.1073/pnas.1206362109. Epub 2012 Aug 29.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Autophagy / drug effects*
  • Blotting, Western
  • Carbamazepine / pharmacology
  • Caspase 3 / metabolism
  • Fluorometry
  • Frontotemporal Dementia / complications*
  • Frontotemporal Dementia / drug therapy*
  • Frontotemporal Dementia / physiopathology
  • In Situ Nick-End Labeling
  • Maze Learning / drug effects
  • Memory Disorders / drug therapy
  • Mice
  • Psychomotor Performance / drug effects
  • Rotarod Performance Test
  • Sirolimus / pharmacology*
  • Sirolimus / therapeutic use
  • Spermidine / pharmacology
  • TDP-43 Proteinopathies / complications*
  • TDP-43 Proteinopathies / drug therapy*
  • TDP-43 Proteinopathies / physiopathology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Tamoxifen / pharmacology

Substances

  • Tamoxifen
  • Carbamazepine
  • TOR Serine-Threonine Kinases
  • Caspase 3
  • Spermidine
  • Sirolimus