Mutant huntingtin crosses the neuromuscular junction and causes transmission-selective pathological alterations in huntingtin expressing myotubes
Dinamarca Ceballos, M.; Colombo, L.; Brykczynska, U.; Grimm, A.; Tousiaki, E. N.; Fruh, I.; Hossain, I.; Gabriel, D.; Eckert, A.; Mueller, M.; Pecho-Vrieseling, E.
Show abstract
A potential explanation for the spatiotemporal accumulation of pathological lesions in the brain of patients with neurodegenerative protein misfolding diseases (PMDs) is cell-to-cell transmission of aggregation-prone, misfolded proteins. Little is known about central to peripheral transmission and its contribution to pathology. We show that transmission of Huntingtons disease- (HD-) associated mutant HTT exon 1 (mHTTEx1) occurs across the neuromuscular junctions in human iPSC cultures and in vivo in wild-type mice. We found that transmission is an active and dynamic process, that happens prior to aggregate formation and is regulated by synaptic activity. Furthermore, we find that transmitted mHTTEx1 causes HD-relevant pathology at a molecular and functional level in human muscle cells, even in the presence of ubiquitous expression mHTTEx1. With this work we uncover a casual-link between mHTTEx1 synaptic transmission and pathology, highlighting the therapeutic potential in blocking toxic protein transmission in PMDs.
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