Huntington's Disease

Huntington's disease (HD) is a neurodegenerative disorder characterized by a triad of motor, cognitive, and psychiatric symptoms. The pathology of HD primarily affects the basal ganglia and cortex, leading to motor symptoms such as chorea, dystonia, and bradykinesia. Cognitive impairment includes deficits in executive function, memory, and attention, while psychiatric symptoms may manifest as depression, anxiety, and psychosis.

HD caused by a mutation in the huntingtin (HTT) gene, leading to the abnormal expansion of a CAG repeat in the gene's coding region. This expanded repeat results in the production of a mutant huntington protein that accumulates in neurons and disrupts their function. Although the disease is triggered by the mutation of a single gene, intensive research has linked numerous other genes to its pathogenesis. Transcription factors such as CBP and p53 are sequestered, VDACs and TOMs are impaired and dopamine and glutamate signalling is distrubed.

HD is inherited in an autosomal dominant manner, meaning that individuals with a single mutant HTT allele are at risk of developing the disease, with symptoms typically appearing in mid-adulthood. Approximately 2.71 people per 100,000 worldwide are affected by the disease. In the following, the biochemical core processes of HD are described and important targets for therapeutic research are presented, alongside with suiting antibodies and proteins to carry on research.

The mutant huntington protein in HD contains an expanded polyglutamine tract, making it prone to misfolding and aggregation.

Transcriptional Dysregulation

Transcription Factor Sequestration: Mutant huntington can sequester essential transcription factors such as CREB-binding protein (CBP) and p53. CBP is a co-activator involved in the regulation of multiple genes critical for neuronal survival and function. Its sequestration by mutant huntington impairs its ability to activate gene expression. Histone Modifications: Mutant huntington can also affect histone acetylation, a critical epigenetic modification that regulates gene expression. It has been shown to reduce histone acetylation levels, leading to condensed chromatin and decreased accessibility of genes for transcription.

Altered Protein Folding

The mutant huntington protein in HD contains an expanded polyglutamine tract, making it prone to misfolding and aggregation. The polyQ stretch is on exon 1, which is cleaved off, with the resulting N-terminal fragment enough to cause aggregation. These aggregated mutant proteins overwhelm the cell's protein degradation machinery, including the ubiquitin-proteasome system and autophagy pathways.

Impaired Protein Degradation

As a result the cell's chaperone network overloads so other metastable proteins misfold, producing a complex loss-of-function phenotype that leads to neurodegeneration. This impaired protein clearance leads to cellular dysfunction and ultimately neuronal death, contributing to the progressive neurodegeneration observed in HD.

Efforts to enhance protein degradation pathways or facilitate the removal of aggregated proteins are promising strategies in HD research, with the potential to alleviate the toxic effects of protein accumulation and slow the progression of the disease.

Mitochondrial Dysfunction

In HD, mitochondria become less efficient at producing energy through oxidative phosphorylation, leading to energy deficits in affected neurons. Mutant huntington protein can interact with and affect the function of several key mitochondrial antigens, such as voltage-dependent anion channels (VDACs) and translocase of the outer membrane (TOM) proteins. These interactions lead to impaired mitochondrial membrane integrity and compromised energy production. Furthermore, antibodies against these mitochondrial antigens have been detected in the blood of HD patients, suggesting an autoimmune response against dysfunctional mitochondria.

This dysfunction results in increased oxidative stress, which damages cells and exacerbates neurodegeneration in HD. Moreover, impaired mitochondrial dynamics and transport disrupt the distribution of healthy mitochondria within neurons, further contributing to their degeneration.

Disrupted Neuronal Circuitry

Mutant huntington protein can directly interfere with various neuronal antigens, resulting in the breakdown of essential connections in the brain. Preferred targets of mutant huntington protein are synaptic vesicle release and neurotransmitter receptors, like the NMDA receptor. They are adversely affected, ultimately impairing synaptic plasticity and connectivity.

Protein Phosphatase 1, Regulatory Subunit 1B (PPP1R1B/DARPP-32) regulates the transmission of dopamine and glutamate signals in striatal neurons. Mutant huntington in HD disrupts the function of DARPP-32, which contributes to abnormal signaling in the striatal circuits. This disruption has direct consequences for motor control and cognitive functions affected in HD.

Another possible target for the mutated huntington protein is the dopamine D2 receptor (DRD2). Altered expression and function of DRD2 can, like DARPP-32, lead to imbalances in dopamine signaling, impacting motor control and potentially contributing to the characteristic chorea seen in HD.

Therapeutic Approaches for HD

The mechanism and modality in which cysteine-adenosine-guanine expansion leads to a poisonous effect on the neuron are yet to be clearly understood. Since HD is an inherited monogenic disorder, lowering the mutant huntingtin represents a promising therapeutic strategy. Huntingtin lowering strategies mostly focus on nucleic acid approaches, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). Currently, no effective remedy has been found for HD, though.

A new approach identifies essential features of the polyQ amyloid nucleus. This pattern encodes a four-stranded steric zipper with interdigitated Q side chains. Once formed, the zipper poisoned its own growth. The self-poisoning may be exploited to block amyloid formation, by genetically oligomerizing polyQ prior to nucleation and thereby decelerate the disease.

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