Huntington’s Disease: Pathogenic Mechanisms and Therapeutic Targets

Abstract

Huntington's disease (HD) is a tandem repeat disorder involving neurodegeneration and a complex combination of symptoms. These include psychiatric symptoms, cognitive deficits culminating in dementia, and the movement disorder epitomised by motor signs such as chorea. HD is caused by a CAG repeat expansion encoding an extended tract of the amino acid glutamine in the huntingtin protein. This polyglutamine expansion appears to induce a 'change of function', possibly a 'gain of function', in the huntingtin protein, which leads to various molecular and cellular cascades of pathogenesis. In the current review, we will briefly describe these broader aspects of HD pathogenesis, but will then focus on specific aspects where there are substantial bodies of experimental evidence, including oxidative stress, mitochondrial dysfunction, glutamatergic dysfunction and neuroinflammation. Furthermore, we will review recent preclinical therapeutic approaches targeting some of these pathogenic pathways, their clinical implications and future directions.

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

“…Huntington disease (HD) is a rare genetic autosomal dominant neurodegenerative syndrome triggered by expanded CAG repeats in the huntingtin gene, which leads to pathological elongation of huntingtin with a polyglutamine tract. The neurodegenerative conditions caused due to HD lead to cognitive, motor, and psychiatric symptoms, atrophy of the basal ganglia and the cerebral cortex (Wright et al, 2017;Illarioshkin et al, 2018). Transcriptional dysregulation has been suggested a prominent mechanism for pathogenesis of HD (Sharma and Taliyan, 2015b).…”

Protein Misfolding and ER Stress in Huntington's Disease

“…HD is a genetic disorder characterized by movement disorder, cognitive decline, and behavioral difficulties (Walker, 2007; Wright et al, 2017; Pandey and Rajamma, 2018). As found in post-mortem and MRI studies, HD patients suffer from neuronal cell death, initially and mostly in the striatum but also in the cortex and other areas of the brain (Reiner et al, 1988; Rosas et al, 2003).…”

“…There is currently no cure or effective therapy for HD. There are two main recent experimental approaches to try to develop a therapy (reviewed in Huang et al, 2016; Wright et al, 2017; Caron et al, 2018; Saavedra et al, 2018). One involves gene therapy, which includes knockdown of mHtt (Aguiar et al, 2017; Datson et al, 2017; Southwell et al, 2018) and expression of miRNAs (Miniarikova et al, 2017; Evers et al, 2018) (Table 1).…”

The Nebraska Educator Volume 4: 2017

“…When processing information, the brain exploits various components to help encode the information and categorize the information into longterm memory. Magnetic resonance imaging (fMRI) data indicates that long-term memory, such as episodic memory and item memory, is active in the hippocampus (Scott, 2017;Wright, Renoir, Gray, & Hannan, 2017). Mergel (1998) showed that long-term memory has an unrestricted capacity.…”