Uncovering hidden protein networks in Huntington's disease: implications for pathogenesis and therapy

Huntington's Disease is a neurodegenerative disorder that progresses over time and can be passed down from parent to child. In uncontrolled motor activities, behavioural problems come into play, as well as progressive mental decline. The CAG triplet in the HTT gene found on chromosome 4 undergoes changes, leading to the production of a mutant protein called huntingtin, which consists of a bigger-than-normal polyglutamine tract that then undergoes misfolding and produces toxic oligomers and fibrillar deposits that can cause dysfunction in normal cell functioning and therefore in nerve cells as well. Although early research linked the pathophysiology of Huntington's disease primarily to mHTT aggregation, more recent research indicates broad protein-protein interaction networks that affect several cellular pathways. Systems biology approaches using tools such as STRING, BioGRID, and Cytoscape have provided evidence of interconnected networks that promote proteostasis, mitochondrial dynamics, energy metabolism, neuroinflammation, synaptic transmission, and transcriptional and epigenetic regulation. Important protein hubs, including HSP70, DRP1, NLRP3, and TFEB, act as central controls that bind those pathways. mHTT-mediated defect in the function of the ubiquitin-proteasome system promotes mitochondrial oxidative stress, which triggers the NLRP3 inflammasome, leading to synaptic dysfunction and specific loss of striatal medium spiny neurons. Investigations using various experimental techniques, which involve R6/2 and YAC128 mouse models, neurons derived from human iPS cells, and multi-omics studies, reveal that faulty neuroplasticity develops before the formation of visible protein aggregates. As for therapeutics targeting central components of neuronal networks, they have all demonstrated certain neuroprotective effects.