Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS

Abstract

Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highlyconserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, the relationship between these phenomena remains poorly defined. Here, we showed that hyperexcitability recapitulates TDP43 pathology by upregulating shortened (s) TDP43 splice isoforms. These truncated isoforms accumulated in the cytoplasm and formed insoluble inclusions that sequestered full-length TDP43 via preserved N-terminal interactions. Consistent with these findings, sTDP43 overexpression was toxic to mammalian neurons, suggesting neurodegeneration arising from complementary gain-and loss-of-function mechanisms. In humans and mice, sTDP43 transcripts were enriched in vulnerable motor neurons, and we observed a striking accumulation of sTDP43 within neurons and glia of ALS patients. Collectively, these studies uncover a pathogenic role for alternative TDP43 isoforms in ALS, and implicate sTDP43 as a key contributor to the susceptibility of motor neurons in this disorder.

Mislocalisation of TDP‐43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex

“…At the same time, mislocalised TDP‐43 influences the expression of thousands of genes, so it is also plausible that mislocalised TDP‐43 could influence both excitatory synapses and intrinsic excitability independently and simultaneously (Amlie‐Wolf et al., 2015; Sephton et al., 2011). To add to the complexity of TDP‐43 induced altered excitability in ALS, a recent study elegantly showed that driving hyperexcitability pharmacologically can cause the mislocalisation of TDP‐43 in human‐induced pluripotent stem cell‐derived motor neurons (Weskamp et al., 2020). This indicates that not only can TDP‐43 mislocalisation cause hyperexcitability, but this in turn may drive more TDP‐43 into the cytoplasm in a positive feedback cycle.…”

Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS

“…Recently, hyperexcitability was found to lead to the expression of two shortened splice isoforms of TDP-43 (sTDP-43-1 and sTDP-43-2), wherein the entire glycine-rich domain of TDP-43 is replaced by short tails generated by the inclusion of a new exon encoding a unique 18-amino acid C-terminus not found in the wild-type full-length TDP-43 (Fig. 2) [111]. The sTDP-43-1 isoform is prone to cytoplasmic localization due to a de novo NES created by the neural activity-dependent splicing.…”

Pathogenic or protective? Neuropeptide Y in amyotrophic lateral sclerosis

“…Cortical hyperexcitability is a highly conserved feature of both sporadic and familial ALS patients (Bae, Simon, Menon, Vucic, & Kiernan, 2013; van den Bos, Geevasinga, Higashihara, Menon, & Vucic, 2019; Geevasinga et al., 2015; Menon et al., 2017), which precedes symptom onset and muscle weakness, and is a strong predictor of disease progression, negatively correlating with the Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised Score (Geevasinga, Menon, Ozdinler, Kiernan, & Vucic, 2016; Menon, Kiernan, & Vucic, 2015; Shibuya et al., 2016; Van den Bos, Menon, et al, 2018). As an important pathophysiological process in ALS, a recent study has shown that hyperexcitability can also drive the emergence of TDP‐43 pathology in vulnerable motor neurons (Weskamp et al., 2020). TDP‐43 is the major pathological protein in ALS.…”