Molecular Pathophysiological Mechanisms in Huntington’s Disease

Abstract

Huntington’s disease is an inherited neurodegenerative disease described 150 years ago by George Huntington. The genetic defect was identified in 1993 to be an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 4. In the following almost 30 years, a considerable amount of research, using mainly animal models or in vitro experiments, has tried to unravel the complex molecular cascades through which the transcription of the mutant protein leads to neuronal loss, especially in the medium spiny neurons of the striatum, and identified excitotoxicity, transcriptional dysregulation, mitochondrial dysfunction, oxidative stress, impaired proteostasis, altered axonal trafficking and reduced availability of trophic factors to be crucial contributors. This review discusses the pathogenic cascades described in the literature through which mutant huntingtin leads to neuronal demise. However, due to the ubiquitous presence of huntingtin, astrocytes are also dysfunctional, and neuroinflammation may additionally contribute to Huntington’s disease pathology. The quest for therapies to delay the onset and reduce the rate of Huntington’s disease progression is ongoing, but is based on findings from basic research.

Therapeutic Strategies in Huntington’s Disease: From Genetic Defect to Gene Therapy

“…Following the identification of the genetic defect, many groups of researchers, using chemical models [ 6 ], various genetic animal models [ 7 ], or complex cell lines mimicking the intercellular signaling and circuitry of the human brain [ 8 ], focused on unraveling the complex mechanisms through which the expression of an abnormal protein (mutant huntingtin, mHtt) leads to the massive cellular degeneration and the loss of synaptic activity in HD. Several vicious pathways have been identified [ 5 ], but the detailed description of these pathways is beyond the scope of this review, which is why they will be only briefly summarized below.…”

“…Furthermore, direct interaction of mHtt aggregates with mitochondrial proteins leads to a decrease in the activity of the electron chain complexes, especially of complexes II, III, and IV, [ 5 , 29 ], and a reduction in the mitochondrial membrane potential, with the opening of the mitochondrial permeability transition pore and release of cytochrome c and apoptosis-inducing factor (AIF), which activate caspase-dependent and caspase-independent pathways of apoptosis [ 12 ].…”

“…In terms of pathology, HD is characterized by a striking atrophy of the caudate nucleus and putamen, with astrogliosis and cell loss in the striatum affecting especially the medium spiny neurons (MSNs), as well as neuronal loss in the cortical layers III, IV and VI in late stages [ 5 ].…”

“…The onset of the disease usually occurs in middle age, peaking between 35 and 50 years of age, when patients develop personality changes, involuntary choreic movements, variable degrees of rigidity, incoordination leading to progressive motor dysfunction, and a series of psychiatric symptoms, such as depression, anxiety, psychosis, obsessive-compulsive disorder, cognitive impairment progressing to dementia, and weight loss, eventually developing life-threatening complications from frequent falls, poor nutrition, infections, or swallowing difficulties leading to aspiration pneumonia [ 1 ]. Due to the higher risk of expansion of the unstable sequence of CAG repeats during mitosis in spermatogenesis compared to oogenesis, paternal transmission may result in earlier onset of symptoms (before the age of 20) and a more severe disease variant, associating parkinsonian features, dystonia, and seizures with a more rapid progression (juvenile HD) [ 1 , 5 ]. However, although a larger CAG repeat size correlates with earlier onset, the size of the CAG repeats explains only about 50% of the variance in age of onset.…”

Applications of CRISPR-Cas9 in Alzheimer’s Disease and Related Disorders

“…The mutated gene has extra poly-glutamine (CAG) repeats, and this causes the production of abnormal, toxic proteins [ 71 ]. To date, there are no treatments for this disorder, and the molecular mechanisms underlying the disease pathogenesis have yet to be uncovered [ 75 ]. Given its mainly genetic causes, HD could be considered the ideal neurodegenerative disease in which to employ CRISPR-Cas9.…”