Phosphorylated and aggregated TDP-43 with seeding properties are induced upon mutant Huntingtin (mHtt) polyglutamine expression in human cellular models.

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.

• Authors: Laurent Coudert, Takashi Nonaka, Emilien Bernard, Masato Hasegawa, Laurent Schaeffer, Pascal Leblanc
• Journal: Cellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 76 Issue 13 Pg. 2615-2632 (Jul 2019) ISSN: 1420-9071 [Electronic] Switzerland
• PMID: 30863908 (Publication Type: Journal Article)

Chemical References

• DNA-Binding Proteins
• HTT protein, human
• Huntingtin Protein
• Peptides
• Prion Proteins
• Protein Aggregates
• TARDBP protein, human
• polyglutamine

Topics

• DNA-Binding Proteins (chemistry, genetics, metabolism)
• Humans
• Huntingtin Protein (genetics, metabolism)
• Inclusion Bodies
• Mutation
• Neuroblastoma (genetics, metabolism, pathology)
• Peptides (metabolism)
• Phosphorylation
• Prion Proteins (genetics, metabolism)
• Protein Aggregates
• Tumor Cells, Cultured