Question

The following is known about the pathogenesis of HD a. The genetic mutation that causes HD was discovered in \(1993 .\) b. The mechanism by which mutant Htt causes neuronal dysfunction is well known. c. Excitotoxicity has been proposed as a pathogenic mechanism, on the basis of the observation that infusion of glutamate-receptor agonists into the brain leads to neuronal death and a phenotype similar to \(\mathrm{HD}\). d. Mitochondrial dysfunction is another leading hypothesis for HAD pathogenesis e. All of the above f. a, c and donly

Short answer

a) The genetic mutation that causes HD was discovered in 1993. b) The mechanism by which mutant Htt causes neuronal dysfunction is well known. c) Excitotoxicity has been proposed as a pathogenic mechanism. d) Mitochondrial dysfunction is another leading hypothesis for HD pathogenesis. e) All of the above. f) a, c, and d only. Answer: f) a, c, and d only.

Step-by-step solution

Begin by understanding the pathogenesis of HD

First, we need to understand the correct information about the pathogenesis of Huntington's Disease. We can then use this knowledge to determine which answer choice is accurate.

Evaluate option a: The genetic mutation that causes HD was discovered in 1993

The genetic mutation that causes HD was indeed discovered in 1993. This option is accurate.

Evaluate option b: The mechanism by which mutant Htt causes neuronal dysfunction is well known

This statement is not entirely correct. While some aspects of the mechanism are known, the exact process by which mutant Htt causes neuronal dysfunction is still being researched.

Evaluate option c: Excitotoxicity has been proposed as a pathogenic mechanism

Excitotoxicity is indeed one of the proposed pathogenic mechanisms for HD, as researchers have found that increased levels of glutamate receptor agonists can lead to neuronal death and a phenotype similar to HD. This option is accurate.

Evaluate option d: Mitochondrial dysfunction is another leading hypothesis for HAD pathogenesis

Mitochondrial dysfunction is indeed another leading hypothesis for HD pathogenesis. Researchers have found evidence that impaired mitochondrial function is involved in the disease. This option is accurate.

Evaluate option e: All of the above

As we have analyzed the options, we know that option (b) is not accurate. Hence option (e) cannot be the correct answer.

Evaluate option f: a, c and d only

Based on our evaluation, options (a), (c), and (d) are accurate statements about the pathogenesis of HD. Therefore, option (f) is the correct answer to this exercise.

Key concepts

Genetic Mutation of HD

Huntington's Disease (HD) is a devastating genetic disorder that leads to progressive deterioration of motor control, cognitive decline, and psychiatric issues. At the heart of its pathogenesis is a genetic mutation that was identified in 1993. This mutation occurs in the HTT gene, which provides instructions for making a protein called huntingtin.

Normal huntingtin plays a crucial role in neurons, but when the gene is mutated, it leads to the production of an altered form of the huntingtin protein. This abnormal protein gradually accumulates inside neurons, causing toxic effects that eventually lead to cell death and symptoms of the disease. What makes the mutation unique is its nature: it involves a DNA segment known as a CAG trinucleotide repeat. A greater number of these repeats correlates with earlier onset and increased severity of the disease.

The mutation's impacts are vast, ranging from direct effects on the brain cells to more subtle influences on cellular processes, making its study a cornerstone in understanding HD.

Neuronal Dysfunction Mechanisms

The mutant huntingtin protein instigates various mechanisms of neuronal dysfunction, which cumulatively contribute to the symptoms seen in patients with Huntington's Disease. Although the full mechanism is still under investigation, scientists have gleaned insights into several critical pathways.

Aberrant protein interactions: The mutated huntingtin protein can bind to other cellular proteins abnormally, disrupting their functions. This can derange multiple cellular processes, such as protein synthesis and transport, ultimately leading to nerve cell dysfunction.

Impaired neuronal signaling: The altered huntingtin protein may also affect the ability of neurons to communicate with each other. Communication is vital for normal brain function, and when signaling pathways go awry, it can exacerbate disease progression.

Gene expression changes: The mutant protein has been shown to interfere with the normal expression of genes in neurons. This can lead to a loss of protective functions and the activation of harmful pathways, culminating in cell death.

Underappreciated until recently, these mechanisms are now targets for novel therapeutic interventions intended to halt or slow the progression of HD.

Excitotoxicity in HD

Excitotoxicity refers to neuronal injury and death caused by excessive stimulation by neurotransmitters such as glutamate. In HD, abnormal glutamate signaling leads to the overactivation of its receptors on neurons, which can cause an influx of calcium and subsequent cell damage. This overstimulation is toxic to cells and is believed to be one of the key contributors to the neuronal degeneration observed in HD.

Researchers have shown that infusions of glutamate-receptor agonists into the brain can mimic symptoms of HD, reinforcing the theory that excitotoxicity plays a role in the disease's pathogenesis. Therefore, treatments that mitigate excitotoxicity provide a promising avenue for reducing neuronal death and ameliorating symptoms in affected individuals.

Mitochondrial Dysfunction in HD

Mitochondria are the powerhouses of the cell and are responsible for generating the energy that cells need to function correctly. However, in Huntington's Disease, mitochondrial dysfunction is a significant aspect of the disease mechanism. The mutated huntingtin protein disrupts normal mitochondrial activity, leading to energy deficits, increased oxidative stress, and the eventual death of neurons.

When mitochondria do not work correctly, it not only affects the energy supply but also leads to the accumulation of damaging reactive oxygen species, which can further harm the cell's components. The link between mitochondrial dysfunction and HD is a critical area of research, as restoring mitochondrial function may offer an effective therapeutic strategy for mitigating the progression of the disease.