TDP-43 is one of the few molecules capable of misfolding and aggregating to produce pathology in the brain. It is a more recently discovered form of proteopathy than the other well-known problem proteins that contribute to neurodegeneration, such as α-synuclein, amyloid-β, and tau. With increased attention given to TDP-43 by the research community, its contribution to the aging of the brain and neurodegenerative conditions is expanding to be broader than first thought. Here, as one example, researchers provide evidence for TDP-43 to be involved in Huntington's disease.
Huntington's disease (HD) is a hereditary neurodegenerative disorder that manifests with movement disturbances, psychiatric changes, and cognitive decline. It is caused by an unstable CAG repeat expansion in exon1 of the huntingtin gene (HTT), which is translated to an abnormally long polyglutamine (polyQ) stretch in the HTT protein. The expanded polyQ repeats lead to aggregation of mutant HTT and the selective neuronal cell loss in the striatum, cortex, and other brain regions in HD patients.
Under normal conditions, TDP-43 is predominantly found in the nucleus, where it regulates gene expression. However, in various pathological conditions, TDP-43 is mislocalized in the cytoplasm. By investigating HD knock-in mice, we explore whether the pathogenic TDP-43 in the cytoplasm contributes to HD pathogenesis, through expressing the cytoplasmic TDP-43 without nuclear localization signal. We found that the cytoplasmic TDP-43 is increased in the HD mouse brain and that its mislocalization could deteriorate the motor and gait behavior.
Importantly, the cytoplasmic TDP-43, via its binding to the intron1 sequence of the mouse HTT precursor messenger RNA (pre-mRNA), promotes the transport of exon1-intron1 HTT onto the ribosome, resulting in the aberrant generation of exon1 HTT. Our findings suggest that cytoplasmic TDP-43 contributes to HD pathogenesis via its binding to and transport of nuclear un-spliced mRNA to the ribosome for the generation of a toxic protein product.
Link: https://doi.org/10.1111/acel.14325
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