The huntingtin protein (HTT) is a large protein found throughout the body, with its highest concentrations in the brain. It is important for the normal operation of nerve cells. A mutation within the HTT gene, which provides instructions for making the protein, causes Huntington’s disease. This inherited condition leads to the progressive degeneration of nerve cells as the genetic alteration changes the protein’s structure and function.
Function of the Normal Huntingtin Protein
In its healthy form, the huntingtin protein performs many tasks for cellular maintenance within the nervous system. One of its roles is facilitating the movement of materials within neurons. It acts as a scaffold to transport vesicles and organelles like mitochondria along microtubules. This process, axonal transport, ensures nerve cells can communicate and maintain their energy supply.
Huntingtin is also active within the cell nucleus, where it influences gene expression. It helps regulate the production of molecules like brain-derived neurotrophic factor (BDNF). BDNF supports neuron survival and growth, and by managing its availability, huntingtin contributes to the health of these cells.
The protein also protects cells from programmed cell death, or apoptosis. By interfering with the signals that trigger this process, normal huntingtin helps maintain neuronal populations. This function is important for embryonic development and the health of the adult brain.
Architectural Features of Wild-Type Huntingtin
The structure of the normal, or wild-type, huntingtin protein is complex and related to its functions. As a large molecule composed of over 3,100 amino acids, its size allows it to interact with many other proteins. The protein’s architecture is highly flexible, enabling it to adapt its shape to bind with different partners.
A defining characteristic of huntingtin’s structure is the presence of HEAT repeats. These recurring structural motifs consist of paired alpha-helices stacked together to form an elongated, flexible scaffold. This nature permits huntingtin to serve as a platform for assembling molecular machinery involved in processes like vesicle transport or gene regulation.
Located near the protein’s N-terminus is a sequence called a polyglutamine tract, which consists of repeated glutamine amino acids. In the healthy protein, this tract is short, containing between 10 and 35 glutamine residues. This length is a normal and stable feature of the protein.
The Huntington’s Disease Mutation and Structural Change
Huntington’s disease arises from a mutation in the HTT gene. The mutation is an expansion of a DNA segment known as a CAG trinucleotide repeat. While the CAG sequence repeats a moderate number of times in the normal gene, it repeats excessively in individuals with the disease, which alters the protein’s structure.
The expanded CAG repeats in the gene create a huntingtin protein with an abnormally long polyglutamine (polyQ) tract. When the number of glutamine residues exceeds 36, the protein’s physical properties change. A count of 40 or more glutamines is considered fully penetrant, meaning it will cause the disease. This elongated polyQ tract destabilizes the protein.
This alteration induces the protein to misfold into an incorrect shape. The misfolded protein is unstable and is cut into smaller pieces by cellular enzymes like caspases and calpains. These enzymes cleave the mutated huntingtin into smaller, toxic fragments. These fragments, containing the expanded polyQ tract, are the agents of cellular damage.
The elongated polyglutamine region has a high tendency to form abnormal structures. The glutamine side chains form hydrogen bonds with each other, causing the protein fragments to aggregate. This process transforms a soluble protein into an insoluble, pathogenic one, initiating neurodegeneration.
Cellular Impact of the Mutated Structure
The mutated huntingtin protein’s altered structure results in a “toxic gain-of-function,” where the protein acquires new, harmful properties. The smaller, misfolded fragments of mutant huntingtin (mHTT) stick to one another, forming dense, insoluble clumps called aggregates. These aggregates accumulate inside neurons, particularly within the nucleus as neuronal intranuclear inclusions.
These aggregates and soluble mHTT fragments interfere with cellular machinery. They sequester other proteins, preventing them from performing their jobs. A significant disruption is to gene transcription, as mHTT fragments bind to transcription factors in the nucleus. This impairs the cell’s ability to produce necessary proteins, including the protective BDNF.
In the cytoplasm, mHTT disrupts axonal transport, the same process the healthy protein facilitates. The movement of mitochondria is impeded, leading to energy deficits and increased oxidative stress. This dysfunction, combined with disrupted waste-clearing processes like autophagy, creates a toxic environment that triggers apoptosis and neuron death. This progressive neuronal loss is most pronounced in the striatum, a brain region involved in motor control, which explains the symptoms of Huntington’s disease.