A new UCLA Health study has discovered in mouse models that genes associated with repairing mismatched DNA are critical in eliciting damages to neurons that are most vulnerable in Huntington’s disease and triggering downstream pathologies and motor impairment, shedding light on disease mechanisms and potential new ways to develop therapies.
Huntington’s disease is one of the most common inherited neurodegenerative disorders that typically begins in adulthood and worsens over time. Patients begin to lose neurons in specific regions of the brain responsible for movement control, motor skill learning, language and cognitive function. Patients typically live 15 to 20 years after diagnosis with symptoms worsening over time. There is no known cure or therapy that alters the course of the disease.
The cause of Huntington’s disease was discovered over three decades ago – a “genetic stutter” mutation involves repeats of three letters of the DNA, cytosine-adenine-guanine (CAG), in a gene called huntingtin. Healthy individuals usually have 35 or fewer CAG repeats, but people inherited with a mutation of 40 or more repeats will develop the disease. The more CAG repeats a person inherits, the earlier the disease onset occurs. However, how the mutation causes the disease remains poorly understood.
A longstanding enigma in Huntington’s disease, however, has been how the mutated protein derived from the huntingtin gene is present in every cell of the body, but the disease appears to selectively affect certain types of neurons in a few brain regions. This mystery is shared between Huntington’s disease and other neurodegenerative brain disorders, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS), albeit different types of neurons are vulnerable to degeneration in each disorder.
Solving this mystery could hold insights into disease mechanisms and therapies. Recently a human genetic study uncovered about a dozen DNA regions in the genome that harbors “modifiers” for Huntington’s disease, which are DNA variants that could hasten or delay the onset of the disease by up to a few years. Intriguingly, these regions contain multiple genes involved in repairing DNA mismatches. However, the mechanistic connections between mismatch DNA repair and selective neuronal vulnerability in Huntington’s disease remain unknown.
The new study from UCLA Health and the Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA, published in the journal Cell, reveals that a distinct subset of mismatch repair genes are key drivers of Huntington’s disease and how the disease affects specific types of neurons.
“We demonstrate the same DNA mismatch repair genes that are modifiers in the Huntington’s disease patients can drive fast-paced disease processes only in the most vulnerable neurons in a mouse model, leading to a cascade of disease phenotypes,” said lead author Dr. X. William Yang, professor of the UCLA Health Department of Psychiatry and Biobehavioral Sciences and the Terry Semel chair in Alzheimer’s Disease Research and Treatment at the Semel Institute.
Besides molecular and pathological benefits, the study also shows targeting DNA repair genes can ameliorate locomotor and gait deficits, improve neuronal synaptic protein levels and reduce glial cell over-reactivity.
“We were surprised to see the potent and sustained effects of targeting these mismatch repair genes in HD mice – the benefit lasts up to 20 months of age in a mouse, which would be comparable to about 60 years in humans”, said Yang. “Our study suggests that these genes are not just disease modifiers, as suggested by the previous studies, but are genetic drivers of Huntington’s disease.”
“These remarkable results demonstrate that a subset of mismatch repair genes is driving disease in vulnerable neurons because they
confer the fastest rate of CAG repeat expansion in these neurons,” said Dr. Yang. “And our study provides mechanistic links that help to bridge modifier genes from patients, mismatch repair gene driven repeat expansion and selective neuronal vulnerability in HD.”
The study provides important therapeutic implications. Moreover, it shows targeting these mismatch repair genes could benefit multiple brain regions, including brain areas with early-onset (striatum) or late-onset (cortex) pathologies. Thus, it implies therapies targeting this disease mechanism could be helpful both in delaying the onset or slowing the progression of the disease.
Additionally, this study demonstrates that an HD mouse model and its constellation of molecular, pathological and behavioral phenotypes could constitute a platform to test novel therapeutics targeting the HD modifier genes involved in CAG repeat expansion or mechanisms improving the resilience or health of HD-vulnerable neurons.
Inherited dynamic DNA repeat mutations affect over 30 neurological disorders and several of them also found mismatch repair genes that could affect the repeat instability or disease severity. The mechanistic findings and model platform could help discover therapies for these other disorders as well.