Developmental and physiological impacts of pathogenic human huntingtin protein in the nervous system

Hana, T. A.; Mousa, V. G.; Lin, A.; Haj-Hussein, R. N.; Michael, A. H.; Aziz, M. N.; Kamaridinova, S. U.; Basnet, S.; Ormerod, K. G.

doi:10.1101/2024.08.30.610525

bioRxiv · 10.1101/2024.08.30.610525

Developmental and physiological impacts of pathogenic human huntingtin protein in the nervous system

Hana, T. A.·Mousa, V. G.·Lin, A.·Haj-Hussein, R. N.·Michael, A. H.·Aziz, M. N.·Kamaridinova, S. U.·Basnet, S.·Ormerod, K. G.

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Abstract

Huntingtons Disease (HD) is a neurodegenerative disorder, part of the nine identified inherited polyglutamine (polyQ) diseases. Most commonly, HD pathophysiology manifests in middle-aged adults with symptoms including progressive loss of motor control, cognitive decline, and psychiatric disturbances. Associated with the pathophysiology of HD is the formation of insoluble fragments of the huntingtin protein (htt) that tend to aggregate in the nucleus and cytoplasm of neurons. To track both the intracellular progression of the aggregation phenotype as well as the physiological deficits associated with mutant htt, two constructs of human HTT were expressed with varying polyQ lengths, non-pathogenic-htt (Q15, NP-htt) and pathogenic-htt (Q138, P-htt), with an N-terminal RFP tag for in vivo visualization. P-htt aggregates accumulate in the ventral nerve cord cell bodies as early as 24 hours post hatching and significant aggregates form in the segmental nerve branches at 48 hours post hatching. Organelle trafficking up-and downstream of aggregates formed in motor neurons showed severe deficits in trafficking dynamics. To explore putative downstream deficits of htt aggregation, ultrastructural changes of presynaptic motor neurons and muscles were assessed, but no significant effects were observed. However, the force and kinetics of muscle contractions were severely affected in P-htt animals, reminiscent of human chorea. Reduced muscle force production translated to altered locomotory behavior. A novel HD aggregation model was established to track htt aggregation throughout adulthood in the wing, showing similar aggregation patterns with larvae. Expressing P-htt in the adult nervous system resulted in significantly reduced lifespan, which could be partially rescued by feeding flies the mTOR inhibitor rapamycin. These findings advance our understanding of htt aggregate progression as well the downstream physiological impacts on the nervous system and peripheral tissues.

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Hana, T. A., Mousa, V. G., Lin, A., Haj-Hussein, R. N., Michael, A. H., Aziz, M. N., Kamaridinova, S. U., Basnet, S., Ormerod, K. G.. 2024-09-02. Developmental and physiological impacts of pathogenic human huntingtin protein in the nervous system. https://doi.org/10.1101/2024.08.30.610525

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