Expression of mutant Huntingtin induces proteasomal defects, mitochondrial abnormalities, and cell death in...

Huntington's disease is an inherited neurodegenerative disorder characterized by the progressive loss of neurons, particularly in the basal ganglia, resulting from a mutation in the Huntingtin gene. Recently, skeletal muscle defects have emerged as a contributing factor in HD pathogenesis. However, the mechanistic role of mutant HTT on muscle abnormality remains elusive. In this study, we sought to elucidate the pathogenesis of Huntington's disease in skeletal muscles using Drosophila melanogaster as a model organism. We employed two transgenic fly lines - HTT.ex1.Q120 expressing the exon 1 fragment of the human HTT gene along with 120 polyQ repeats and mRFP-HTT.588.Q138 expressing 588 amino acids at the N-terminal of the human HTT gene along with 138 polyQ repeats. We combined behavioural, molecular, and imaging techniques to study the effect of mutant HTT on skeletal muscles. When mutant HTT proteins are expressed in the indirect flight muscles, these flies exhibited severe defects, including reduced climbing and locomotor abilities and a significantly shortened lifespan. These phenotypes were associated with the formation of mHTT aggregates in the muscles. Furthermore, we found that mitochondrial integrity is compromised, as evidenced by abnormal mitochondrial morphology. Additionally, increased proteasomal dysfunction and apoptosis were observed in the muscles of flies expressing HTT.ex1.Q120 and mRFP-HTT.588.Q138. The study offers valuable insights into muscle pathogenesis in Huntington's disease and suggests that skeletal muscle may represent a major peripheral contributor to disease progression. It highlights the need for further investigation into the pathogenesis of skeletal muscle to develop HD therapeutics.