Specific nerve cells lost early in Huntington’s disease course: Study
Results may inform future studies on disease progression
A type of brain nerve cells called layer 5a pyramidal neurons — especially those projecting into the striatum, a brain region greatly affected in Huntington’s disease — are lost early in the course of Huntington’s, a study found.
Excessive CAG repeats in the HTT gene, the cause of Huntington’s, were detected in these vulnerable neurons, as well as neighboring neurons that remained resilient, or alive, during these early phases of the disease.
This, along with findings of altered neuronal communication in layer 5a pyramidal neurons, suggests that both CAG repeat expansion and changes to how these neurons communicate may contribute to their vulnerability, the researchers noted.
These results may “enable additional comparative studies to gain insight into specific aspects of HD [Huntington’s disease] progression and into general questions surrounding selective cellular vulnerability in human disease,” the researchers wrote.
The study, “Selective vulnerability of layer 5a corticostriatal neurons in Huntington’s disease,” was published in the journal Neuron.
Sorting brain cells for patterns
The HTT gene, which codes for a protein called huntingtin, contains CAG repeats, a series of three DNA building blocks that are repeated 10 to 35 times in a row. But in Huntington’s, these CAG repeats are present ate excessive numbers, often 40 or more.
The result is an abnormally long and toxic version of the huntingtin protein that builds up in neurons, causing symptoms. The more CAG repeats, the earlier the age at which symptoms first start.
Stretches of CAG repeats can get longer in cells over a person’s lifetime, a process called somatic expansion. They also can vary in length from cell to cell. Which neurons are most vulnerable to somatic expansion, however, is unclear.
To know more, the researchers turned to a technique called serial fluorescence-activated nuclear sorting (sFANS) to sort different types of brain cells and study the content of their nuclei, where all DNA is stored. The goal was to watch for distinctive patterns linked to Huntington’s, especially in neurons that appeared most vulnerable.
They were able to isolate nuclei from up to 16 different types of cells from five regions of the brain’s cortex of 13 deceased people with early-stage Huntington’s.
The cortex is the brain’s outermost layer, and can be divided in several regions based mostly on the functions they control. For instance, the motor cortex controls the body’s movements.
The cortex is composed of six layers, from the outmost layer 1 to the deepest layer 6. Each cortical layer had a characteristic distribution of different neurons and their connections with other cortical regions and other brain regions.
Missing neurons
The team found that layer 5a pyramidal, or pyramid-shaped, neurons were largely missing from the brain’s motor cortex in early-stage Huntington’s patients. Neurons in layer 5a often project to the striatum, a region of the deep brain connected to motor control and cognition that is greatly affected by Huntington’s.
Retrograde tracing, a technique used to determine the location of the nerve cells of origin of a nervous system pathway, in macaque brains confirmed that the vulnerable layer 5a pyramidal neurons connected the cortex and striatum.
Although layer 5a pyramidal neurons in the motor cortex were the most vulnerable, extensive somatic CAG expansion was detected not only in these neurons, but also in Betz cells (a type of giant pyramidal neurons found in layer 5) and neurons in layers 6a and 6b of the motor cortex.
The researchers then compared the activity of molecular pathways between vulnerable layer 5a pyramidal neurons and resilient layer 6a and 6b pyramidal cells with comparable CAG repeat expansions.
In both vulnerable and resilient pyramidal cells, there was reduced activity of pathways involved in processes needed for the healthy function of dendrites and synapses, two neuronal projections essential for nerve cell communication.
Layer 5a pyramidal neurons also showed increased activity in genes involved in delivery of cell surface proteins to their sites in the membrane, which may also influence nerve cell communication.
The data “indicate that altered synaptic function of L5a and, perhaps, L6 deep layer neurons may result in their dysfunction, and they suggest that altered corticostriatal connectivity may play an important role in the selective loss of L5a corticostriatal pyramidal cells in HD,” the researchers wrote.
“We propose that enhanced somatic [mutant HTT] CAG expansion and altered synaptic function act together to cause corticostriatal disconnection and selective neuronal vulnerability in HD cerebral cortex,” the team wrote. “Additional studies will be required to assess variable loss of specific cell subpopulations in HD and to determine whether differences in the frequency of very long CAG repeats … correlates with the selective vulnerability of L5a neurons,” they wrote.
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