Huntington’s Disease—An Outlook on the Interplay of the HTT Protein, Microtubules and Actin Cytoskeletal Components

Abstract

Huntington’s disease is a severe and currently incurable neurodegenerative disease. An autosomal dominant mutation in the Huntingtin gene (HTT) causes an increase in the polyglutamine fragment length at the protein N-terminus. The consequence of the mutation is the death of neurons, mostly striatal neurons, leading to the occurrence of a complex of motor, cognitive and emotional-volitional personality sphere disorders in carriers. Despite intensive studies, the functions of both mutant and wild-type huntingtin remain poorly understood. Surprisingly, there is the selective effect of the mutant form of HTT even on nervous tissue, whereas the protein is expressed ubiquitously. Huntingtin plays a role in cell physiology and affects cell transport, endocytosis, protein degradation and other cellular and molecular processes. Our experimental data mining let us conclude that a significant part of the Huntingtin-involved cellular processes is mediated by microtubules and other cytoskeletal cell structures. The review attempts to look at unresolved issues in the study of the huntingtin and its mutant form, including their functions affecting microtubules and other components of the cell cytoskeleton.

Gene Expression Profiling in Huntington’s Disease: Does Comorbidity with Depressive Symptoms Matter?

“…HTT is an important protein for neurodevelopment. The knockout of the HTT in mice results in major brain abnormalities and death soon after birth [ 4 , 5 , 6 ]. In addition, depletion of wild-type HTT in the postnatal mouse brain leads to progressive neurodegeneration [ 7 ].…”

Distinct subcellular autophagy impairments in induced neurons from patients with Huntington's disease

“…Moreover, lysosome transport is also mediated via microtubules in the neurites. 69 To investigate a direct link between the reduced neurite morphology in HD-iNs and autophagy, we analysed neuronal morphology after inhibition or activation of autophagy using Baf or W and starvation, respectively. We found a significant reduction in the ctrl-iNs neurite area and length when inhibiting autophagy using Baf or W. In contrast, HD-iNs did not exhibit any further reduction in neurite area or length after autophagy suppression ( Fig.…”

“…Energy impairments such as decreased mitochondrial biogenesis and trafficking, oxidative stress, increased apoptosis, and ATP deficit all have been implicated in Huntington's disease pathogenesis. 69 Neurons are energetically demanding cells and thus highly vulnerable to abnormalities in cellular respiration. Our findings point towards boosting autophagy by specifically targeting the AMPK pathway.…”

Distinct sub-cellular autophagy impairments occur independently of protein aggregation in induced neurons from patients with Huntington’s disease

“…Autophagosomes form at the axon terminal and fuse with lysosomes during a dynein-mediated transport to the soma. Moreover, lysosome transport is also mediated via microtubules in the neurites (49). To investigate a direct link between the reduced neurite morphology in HD-iNs and autophagy, we analyzed neuronal morphology after inhibition or activation of autophagy using Baf or W and starvation, respectively.…”

“…AMPK inhibits cell growth by inhibiting mTORC signaling and protein synthesis downstream of mTORC1. Energy impairments such as decreased mitochondrial biogenesis and trafficking, oxidative stress, increased apoptosis, and ATP deficit all have been implicated in HD pathogenesis (49). Neurons are energetically demanding cells and thus highly vulnerable to abnormalities in cellular respiration.…”