Transmission-selective muscle pathology induced by active propagation of mutant huntingtin across the human neuromuscular synapse

Abstract

Skeletal muscle dysfunction, wasting and synaptic pathology is a hallmark of Huntingtons disease (HD). Similar as for the nervous system the pathological lesions and clinical symptoms progressively worsen with disease coarse. Cell-to-cell transmission of toxic mutant huntingtin (mHTT) has been shown to occur and could be a potential explanation for the progressive accumulation of pathological lesions and clinical symptoms in time. However, the mechanism and contribution of mHTT cell-to-cell transmission to pathology in an environment of ubiquitous expression of the mutant protein is not well understood. Here, we show that the HD-associated mHTT exon 1 (mHTTEx1) is transmitted from human induced pluripotent stem cell- (hiPSC-) derived motor neurons (MNs) to isogenic hiPSC-derived myotubes across functionally active neuromuscular junctions (NMJ) and in vivo in wild-type mice from the M1 motor cortex to spinal MNs and skeletal muscles. Increased synaptic connectivity and activity enhances transmission. Also, our data reveals that transmission happens prior to aggregate formation and that aggregation occurs progressively with continuous transmission across weeks at the myotube surface. Furthermore, we provide evidence that mHTTEx1 derived from MNs causes defragmentation of mitochondria and exacerbates nuclear aggregation, the latter in the presence of myotube autonomous mHTTEx1. Finally, we find that mHTTEx1 transmission results in decreased myotube contractions, in contrast myotube autonomous expression causes a hyperexcitable-like phenotype. Altogether, our data suggests that mHTTEx1 neuromuscular transmission contributes to skeletal muscle dysfunction in HD, via continuous transmission of the toxic protein already at early preclinical stages of HD and thereby contributes to an increasing accumulation of toxic protein in skeletal muscle, eventually leading to a highly-selective phenotype resulting in a decline of skeletal muscle function. Since multiple studies support a role of synaptic transmission of diverse misfolded proteins, including tau in Alzheimers, alpha-synuclein in Parkinsons, mHTT in HD, tdp-43 in Amyotrophic lateral sclerosis and frontotemporal lobar dementia, in the central nervous system, this process likely represents a common synaptic-linked pathobiological pathway for most neurodegenerative protein misfolding diseases.