Understanding DNA expansion in Huntington's disease neurons

This study reveals how gradual expansion of CAG repeats in neurons promotes the development of Huntington's disease, providing new insights into potential therapeutic interventions.

study: Expansion of long somatic DNA repeats drives neurodegeneration in Huntington's disease. Image credit: Shutterstock AI / Shutterstock.com

Recent research published in cell revealed that the repetitive DNA sequences that cause Huntington's disease (HD) slowly expand over decades within disease-specific neurons, ultimately leading to the generation of these neurons and the onset of the disease. .

What causes HD?

HD is a life-threatening neurodegenerative disease that is typically caused by the inheritance of DNA triplet repeats (CAGs)._n in exon 1 of hunting chin (HTT)gene. This CAG repeat encodes a polyglutamine tract within the HTT protein and is involved in regulating gene expression, transporting materials between neurons, and protecting against cell death.

Compared to healthy individuals with 15 to 30 consecutive CAGs, HD patients typically have germline alleles of 36 to 55 consecutive CAGs, and approximately 90% of these individuals have between 40 and 40 of these CAGs. I have inherited 49 pieces.

For decades, HD patients do not show any symptoms. However, usually between the ages of 40 and 50, HD patients develop chorea. Chorea refers to the uncontrollable movements that are characteristic of HD, and often progresses to severe functional impairment, rigidity, and death, along with cognitive and psychiatric symptoms.

Gradual neuronal degeneration caused by CAG expansion

Despite existing evidence regarding the genetic basis of HD, it remains unclear what causes the disease. mutation It induces degeneration of specific neurons only in middle age, after a biological latency period of several decades.

To investigate this phenomenon, the researchers in the current study used single-nuclear ribonucleic acid (RNA) sequencing (snRNA-seq) to analyze the anterior region of the caudate nucleus, the largest part of the striatum. We analyzed RNA expression in 581,273 nuclei isolated from the region. Areas of the brain most frequently affected in HD patients. Caudate nucleus samples were obtained from 50 HD patients and 53 unaffected controls, with an average of 5,643 nuclei obtained from each donor.

The CAG age product (CAP) score, which is often used to estimate the onset and progression of HD, was also used in the analysis. To this end, HD patients with CAP scores up to 300 have a slightly lower proportion of striatal projection neurons (SPNs) compared to healthy controls, and patients with CAP scores >350 have a lower amount of SPNs. It has decreased significantly.

In particular, HD patients without clinical motor symptoms are typically given a CAP score of up to 300, whereas patients with a CAP score of 350 or higher have symptoms of HD. HD patients with a CAP score of 600 or higher often reflect patients with advanced caudate atrophy, who have lost 80-99% of their SPNs, which is associated with increasingly severe HD manifestations. This shows gradual degeneration of the caudate nucleus.

In addition to SPN, the researchers also observed differential expression of thousands of genes in all caudate cell types between individuals with and without HD. This finding exemplifies the severe destruction of the caudate nucleus that occurs in HD.

CAG repeat is HTT There was a somatic increase in genes from 40 to more than 500 in SPN. Expansion of somatic cells from 40 to 150 CAGs did not significantly affect neuronal health. However, expansion of more than 150 CAGs leads to the loss of positive and then negative features of neuronal identity, distorting gene expression, and ultimately degenerating SPNs.

We applied computational extrapolation of data to determine the rate and timing of CAG repeat expansion in SPNs. To this end, we observed a slow initial expansion that occurs less than once per year during the first 20 years of life.

Typically, after a few decades, when a neuron acquires 80 CAG repeats, the rate of expansion increases significantly, expanding to 150 CAG in just a few more years. After a few months, the neurons die.

These findings suggest that SPNs spend more than 95% of their lives with harmless substances. HTT gene. Different neurons reach the toxic threshold of CAG repeats at different times, causing neurons to collectively disappear slowly over a long period of time. This loss usually begins about 20 years before symptoms appear and disappears more rapidly after symptoms begin.

Significance of research

The findings provide important insights into the pathophysiology of HD, as well as other diseases that may be caused by abnormal numbers of DNA repeats, such as fragile X syndrome and myotonic dystrophy. Encouraged by these findings, researchers in the current study are now investigating how more than 150 CAG repeats can lead to neurological dysfunction and death, as well as the role of DNA repeat expansions in other similar genetic diseases and cellular We are investigating the relationship with change.

We can piece together the complete trajectory of pathology unfolding over decades in individual neurons, thereby providing potentially many different time points at which we can intervene therapeutically. ”