AUTHOR=Dinamarca Margarita C. , Colombo Laura , Brykczynska Urszula , Grimm Amandine , Fruh Isabelle , Hossain Imtiaz , Gabriel Daniela , Eckert Anne , Müller Matthias , Pecho-Vrieseling Eline TITLE=Transmission-selective muscle pathology induced by the active propagation of mutant huntingtin across the human neuromuscular synapse JOURNAL=Frontiers in Molecular Neuroscience VOLUME=16 YEAR=2024 URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2023.1287510 DOI=10.3389/fnmol.2023.1287510 ISSN=1662-5099 ABSTRACT=

Neuron-to-neuron transmission of aggregation-prone, misfolded proteins may potentially explain the spatiotemporal accumulation of pathological lesions in the brains of patients with neurodegenerative protein-misfolding diseases (PMDs). However, little is known about protein transmission from the central nervous system to the periphery, or how this propagation contributes to PMD pathology. To deepen our understanding of these processes, we established two functional neuromuscular systems derived from human iPSCs. One was suitable for long-term high-throughput live-cell imaging and the other was adapted to a microfluidic system assuring that connectivity between motor neurons and muscle cells was restricted to the neuromuscular junction. We show that the Huntington's disease (HD)-associated mutant HTT exon 1 protein (mHTTEx1) is transmitted from neurons to muscle cells across the human neuromuscular junction. We found that transmission is an active and dynamic process that starts before aggregate formation and is regulated by synaptic activity. We further found that transmitted mHTTEx1 causes HD-relevant pathology at both molecular and functional levels in human muscle cells, even in the presence of the ubiquitous expression of mHTTEx1. In conclusion, we have uncovered a causal link between mHTTEx1 synaptic transmission and HD pathology, highlighting the therapeutic potential of blocking toxic protein transmission in PMDs.