Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 76 (13), 2615-2632

Phosphorylated and Aggregated TDP-43 With Seeding Properties Are Induced Upon Mutant Huntingtin (mHtt) Polyglutamine Expression in Human Cellular Models

Affiliations

Phosphorylated and Aggregated TDP-43 With Seeding Properties Are Induced Upon Mutant Huntingtin (mHtt) Polyglutamine Expression in Human Cellular Models

Laurent Coudert et al. Cell Mol Life Sci.

Abstract

The Tar DNA-Binding Protein 43 (TDP-43) and its phosphorylated isoform (pTDP-43) are the major components associated with ubiquitin positive/Tau-negative inclusions found in neurons and glial cells of patients suffering of amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration-TDP-43 (FTLD-TDP). Many studies have revealed that TDP-43 is also in the protein inclusions associated with neurodegenerative conditions other than ALS and FTLD-TDP, thus suggesting that this protein may be involved in the pathogenesis of a variety of neurological disorders. In brains of Huntington-affected patients, pTDP-43 aggregates were shown to co-localize with mutant Huntingtin (mHtt) inclusions. Here, we show that expression of mHtt carrying 80-97 polyglutamines repeats in human cell cultures induces the aggregation and the phosphorylation of endogenous TDP-43, whereas non-pathological Htt with 25 polyglutamines repeats has no effect. Mutant Htt aggregation precedes accumulation of pTDP-43 and pTDP-43 co-localizes with mHtt inclusions reminding what it was previously described in brains of Huntington-affected patients. Detergent-insoluble fractions from cells expressing mHtt and containing mHtt-pTDP-43 co-aggregates can function as seeds for further TDP-43 aggregation in human cell culture. The human cellular prion protein PrPC was previously identified as a negative modulator of mHtt aggregation; here, we show that PrPC-mediated reduction of mHtt aggregation is tightly correlated with a decrease of TDP-43 aggregation and phosphorylation, thus confirming the close relationships between TDP-43 and mHtt.

Keywords: ALS; Huntingtin; Huntington; Phosphorylation; Prion; Seeds; TDP-43.

Similar articles

See all similar articles

Cited by 1 PubMed Central articles

Feedback