The huntingtin protein, often abbreviated as HTT, is a large protein found throughout the body, with its highest concentrations in the brain. It plays a role in various cellular processes and is broadly distributed across different tissues, but its specific activities within nerve cells are particularly noteworthy. Proper functioning of HTT is important for cell survival and overall brain health.
The Huntingtin Protein’s Healthy Functions
The normal huntingtin protein performs several roles within cells, especially neurons. It is involved in the development of the nervous system, with its absence being lethal in mouse models, highlighting its fundamental importance. The protein helps transport materials within cells, associating with vesicles and microtubules. This includes movement of organelles like mitochondria along axons and dendrites.
Beyond transport, huntingtin also contributes to synaptic function. It influences gene expression, specifically upregulating the production of brain-derived neurotrophic factor (BDNF), a protein that supports the survival and growth of neurons. The protein also interacts with numerous other proteins, integrating various biochemical pathways within the cell.
The Genetic Basis of Dysfunction
The huntingtin protein is produced based on instructions from the HTT gene, located on chromosome 4. Problems with the huntingtin protein begin with a genetic alteration within this gene: an abnormal expansion of a CAG trinucleotide repeat sequence. This sequence is composed of the DNA building blocks cytosine, adenine, and guanine, repeated multiple times.
In individuals with this genetic alteration, the CAG segment is significantly longer than normal, typically exceeding 36 repeats. This expanded CAG segment leads to the production of an abnormally long version of the huntingtin protein, which contains an extended stretch of the amino acid glutamine. This elongated, altered protein is the underlying cause of Huntington’s disease.
How Mutated Huntingtin Harms Cells
The abnormally long huntingtin protein, due to its expanded glutamine tract, misfolds and accumulates within cells, particularly neurons. These misfolded proteins tend to clump together, forming aggregates or inclusion bodies, which disrupt normal cellular processes. This aggregation is believed to contribute to the toxicity observed in affected cells.
The presence of mutated huntingtin can impair cellular functions, including energy production. It can cause mitochondrial dysfunction, affecting mitochondrial movement and leading to bioenergetic failure. The mutated protein also interferes with the cell’s waste disposal mechanisms, inhibiting normal cleaning processes and leading to cellular waste accumulation.
Furthermore, it disrupts axonal transport, the system that moves essential materials along nerve cells, resulting in neuronal degeneration. The altered protein can also negatively impact gene transcription, affecting the regulation of genes involved in neuronal survival. These disruptions collectively lead to the progressive degeneration and death of neurons, particularly in brain regions like the striatum and cerebral cortex.
Advancing Understanding and Treatments
Current scientific efforts focus on understanding how mutated huntingtin protein causes cellular harm to inform therapeutic strategies. Research investigates how the expanded CAG repeat leads to protein misfolding, aggregation, and cellular dysfunctions. This deepened understanding is driving the development of new interventions.
Promising areas of research include gene silencing therapies, such as antisense oligonucleotides (ASOs) and RNA interference (RNAi). These approaches aim to reduce the production of the abnormal huntingtin protein by targeting its messenger RNA (mRNA) or even the HTT gene itself. Other avenues involve small molecule drugs designed to inhibit protein aggregation or to selectively lower mutant huntingtin levels, with some compounds showing promise in preclinical studies. Neuroprotective strategies, which shield neurons from damage, and stem cell research, which explores replacing damaged cells or providing supportive factors, also offer potential for future treatments. These advancements collectively offer hope for developing effective therapies and improving outcomes for individuals affected by this condition.