From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington's Disease Research

Abstract

Huntington's disease (HD) is a debilitating neurodegenerative genetic disorder caused by an expanded polyglutamine-coding (CAG) trinucleotide repeat in the huntingtin (HTT) gene. HD behaves as a highly penetrant dominant disorder likely acting through a toxic gain of function by the mutant huntingtin protein. Widespread cellular degeneration of the medium spiny neurons of the caudate nucleus and putamen are responsible for the onset of symptomology that encompasses motor, cognitive, and behavioural abnormalities. Over the past 150 years of HD research since George Huntington published his description, a plethora of pathogenic mechanisms have been proposed with key themes including excitotoxicity, dopaminergic imbalance, mitochondrial dysfunction, metabolic defects, disruption of proteostasis, transcriptional dysregulation, and neuroinflammation. Despite the identification and characterisation of the causative gene and mutation and significant advances in our understanding of the cellular pathology in recent years, a disease-modifying intervention has not yet been clinically approved. This review includes an overview of Huntington's disease, from its genetic aetiology to clinical presentation and its pathogenic manifestation. An updated view of molecular mechanisms and the latest therapeutic developments will also be discussed.

Keywords: Huntington’s disease; pathogenesis; therapeutics.

Figure 1

Coronal section of the human brain outlining the basal ganglia. Major signalling pathways of the basal ganglia include the direct, indirect, and hyperdirect pathways. The direct and hyperdirect pathways coordinate excitation of the cerebral cortex. The indirect pathway inhibits cortical excitation. In HD, the medium spiny neurons of the striatum projecting into the globus pallidus are degenerated. GPe, globus pallidus externa; GPi, globus pallidus interna; SN, substantia nigra; STN, subthalamic nucleus. Created with BioRender.com (accessed on 14 January 2023).

Figure 2

Huntingtin structure and processing. The huntingtin gene (HTT) contains 67 exons that are processed to form two mRNA transcripts of 10,366 bp and 13,711 bp that differ in an additional 3′UTR sequence of 3360 bp. Alternative splicing generates several HTT isoforms and transcripts lacking exons 10, 12, 29, and 46 or retaining a 57 bp portion of intron 28. Huntingtin protein is comprised of an N-terminal region that encompasses a 17 amino acid huntingtin nuclear export signal, the polyglutamine repeat (polyQ), and a proline rich domain. The remainder of the protein is organised into clusters of anti-parallel alpha-helical HEAT repeats. Proteolytic cleavage of N-terminal fragments by endoproteases, caspases and calpains occurs more frequently in HD, and it has been proposed that these N-terminal fragments are involved in disease pathogenesis.

Figure 3

Proposed HD pathogenic mechanisms This figure shows possible Huntington disease mechanisms and the cellular location of the aberrant activity including excitotoxicity, dopamine imbalance, mitochondrial dysfunction, disruption of proteostasis, initiation of apoptotic pathways, transcriptional dysregulation, and neuroinflammation. Created with BioRender.com (accessed on 17 August 2023).

Figure 4

150 years of Huntington’s disease research showcasing research milestones.