The interaction between soluble forms of mutant huntingtin protein and key cellular organelles drives the initial steps of the progression of Huntington disease (HD), according to a new study published in the journal Cellular and Molecular Life Sciences. Moreover, the transmission of these mutant huntingtin proteins through exosomes contributes to the spread of the disease in a noncell autonomous manner.
“Our study sheds light into key questions that remained unclear in HD patients,” the researchers wrote. “These findings will provide a novel conceptual framework for the development of effective therapeutic strategies for a devastating disorder with no cure to date.”
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To investigate disease pathogenesis in a physiologically relevant context, the team transplanted neural progenitor cells derived from human pluripotent stem cells from patients with HD and healthy controls into the brain of newborn mice.
Most of these cells differentiated into striatal neurons and projected to their target areas establishing synaptic connections within the basal ganglia circuitry of the animals.
The striatal neurons derived from stem cells obtained from patients with HD first developed soluble forms of mutant huntingtin. These primarily targeted the membranes of the endoplasmic reticulum, mitochondria, and nucleus and caused structural changes.
Moreover, these cells secreted extracellular vesicles that contained mutant huntingtin monomers and oligomers. These were internalized by nonmutated mouse striatal neurons and caused their death.
“We reveal here different aspects of HD human pathogenesis in vivo, allowing [us] to elucidate the primary drivers of disease progression in patients,” the researchers concluded.
HD is an inherited neurological disorder characterized by the accumulation of mutant huntingtin protein and the degeneration of striatal neurons. It is caused by a trinucleotide repeat expansion in the huntingtin gene.
This article originally appeared on Rare Disease Advisor
Miguez A, Gomis C, Vila C, et al. Soluble mutant huntingtin drives early human pathogenesis in Huntington’s disease. Cell Mol Life Sci. Published online August 3, 2023. doi:10.1007/s00018-023-04882-w