English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Open

Presents the pdf analysis as premium feature

PDF Analysis

Insights

Presents the summarisation as premium feature

Summarisation

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the zaia usage as premium feature

ZAIA

Zendy Tools

Zendy Plus

Presents the access of premium content as premium feature

Premium Content

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.

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