Probing the morphological and mechanical changes in a C. elegans model of Huntington's disease.

Abstract

Huntington's Disease (HD) is a fatal neurodegenerative disease caused by a mutation in the huntingtin gene, in which CAG nucleotides are excessively repeated. In turn, translated huntingtin protein (htt) contains an expanded polyglutamine (polyQ) domain, which triggers toxic protein aggregation, the hallmark feature of this disease. Common symptoms of HD, such as chorea, muscle atrophy, and behavioral and neurological decline, continue to worsen as the disease progresses. This study aims to investigate the relationship between polyQ domain length and age-dependent morphological and mechanical changes in a Caenorhabditis elegans model of HD. C. elegans are an established model species to investigate aging, as morphological and mechanical changes—such as epidermal roughening and whole body decrease in Young's modulus, respectively—occur as a function of age. Moreover, worm mobility exhibits a deficit as a result of such changes. We expect to observe age-dependent morphological changes much earlier in the pathogenic C. elegans (Q128), as opposed to age-matched, non-pathogenic C. elegans (Q15). Morphological analysis was performed using tapping mode atomic force microscopy (AFM), and images were processed using custom MATLAB scripts to determine RMS roughness. Further studies will be conducted to investigate the role of age-dependent changes in mechanical properties, such as Young's modulus, as they relate to polyQ domain length. In-situ contact mode AFM will be used to achieve this. We expect to observe age-dependent mechanical changes much earlier in the Q128 worms, in comparison to the Q15 worms. Pending results, additional studies may be conducted to determine if these changes serve as a peripheral biomarker of HD, as well as the role of such a biomarker in diagnostic, prognostic, and therapeutic strategies.