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 journalArticle

12 Citations (Scopus)

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)
Article numberddv193
Pages (from-to)4625-4635
Number of pages11
JournalHuman Molecular Genetics
Volume24
Issue number16
DOIs
StatePublished - Apr 28 2015

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Frontotemporal Dementia
Amyotrophic Lateral Sclerosis
Transgenic Mice
Autophagy
Proteasome Endopeptidase Complex
Proteins
Frontotemporal Lobar Degeneration
Gene Dosage
Memory Disorders
Short-Term Memory
Neurodegenerative Diseases
Cytosol
Cognition

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Reduced protein turnover mediates functional deficits in transgenic mice expressing the 25 kDa C-terminal fragment of TDP-43. / Caccamo, Antonella; Shaw, Darren M.; Guarino, Francesca; Messina, Angela; Walker, Aaron W.; Oddo, Salvatore.

In: Human Molecular Genetics, Vol. 24, No. 16, ddv193, 28.04.2015, p. 4625-4635.

Research output: Contribution to journalArticle

Caccamo, Antonella ; Shaw, Darren M. ; Guarino, Francesca ; Messina, Angela ; Walker, Aaron W. ; Oddo, Salvatore. / Reduced protein turnover mediates functional deficits in transgenic mice expressing the 25 kDa C-terminal fragment of TDP-43. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 16. pp. 4625-4635.
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