Reduced protein turnover mediates functional deficits in transgenic mice expressing the 25 kDa C-terminal fragment of TDP-43

Antonella Caccamo, Darren M. Shaw, Francesca Guarino, Angela Messina, Aaron W. Walker, Salvatore Oddo

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP) are two neurodegenerative disorders characterized by the accumulation of TDP-43. TDP-43 is proteolitically cleaved to generate two major C-terminal fragments of 35 and 25 kDa. The latter, known as TDP-25, is a consistent feature of FTLD-TDP and ALS; however, little is known about its role in disease pathogenesis. We have previously developed transgenic mice overexpressing low levels of TDP-25 (TgTDP-25+/0), which at 6 months of age show mild cognitive impairments and no motor deficits. To better understand the role of TDP-25 in the pathogenesis of ALS and FTLD-TDP, we generated TDP-25 homozygous mice (TgTDP-25+/+), thereby further increasing TDP-25 expression. We found a gene-dosage effect on cognitive and motor function at 15 months of age, as the TgTDP-25+/+ showed more severe spatial and working memory deficits as well as worse motor performance than TgTDP-25+/0 mice. These behavioral deficits were associated with increased soluble levels of TDP-25 in the nucleus and cytosol. Notably, high TDP-25 levels were also linked to reduced autophagy induction and proteasome function, two events that have been associated with both ALS and FTLD-TDP. In summary, we present strong in vivo evidence that high levels of TDP-25 are sufficient to cause behavioral deficits and reduce function of two of the major protein turnover systems: autophagy and proteasome. These mice represent a new tool to study the role of TDP-25 in the pathogenesis of ALS and FTLD-TDP.

Original languageEnglish (US)
Pages (from-to)4625-4635
Number of pages11
JournalHuman molecular genetics
Volume24
Issue number16
DOIs
StatePublished - Apr 28 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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