HMS researchers have used gene therapy to prolong the survival of striatal cells modeled for Huntington’s disease. The therapy targeted the diseased cells’ impaired ability to degrade mutated huntingtin protein, which can accumulate and become toxic. By overexpressing a particular subunit on proteasomes, the neuroscientists increased protein degradation and made cells more resistant to chemical stressors. The findings are reported in the Feb. 28 issue of PloS ONE.
McLean researcher Ole Isacson, HMS professor of neurology, previously found low proteasome activity in brain and skin cells from Huntington’s patients. “Clearly it seemed the proteolytic activity of the system was reduced all over the brain and in skin,” said Isacson of the 2004 study published in Annals of Neurology. But the researchers did not know why the Huntington’s cells had impaired protein breakdown.
In many ways proteasomes look and behave like garbage disposals. The protein-chopping organelle has a hollow core that traps proteins targeted for recycling. Bladelike enzymes line the core while enzyme gates called proteasome activators (PAs) hasten the movement of the targeted proteins into the catalyzing core. In the 2004 study, Isacson increased protein degradation in healthy skin cells by increasing function of the PA28 enzyme with the overexpression of its alpha and beta subunits. But the PA28 subunit treatment did not work in skin cells from Huntington’s patients. The team wondered whether a different subunit would be effective in Huntington’s disease cells and whether striatal neurons—where the huntingtin mutation inflicts the most damage—would be sensitive to the protein-disposing acceleration of PA treatment.
To devise ways to boost protein clearance in Huntington’s, Isacson obtained striatal cells derived from mouse stem cells that were modeled for the disease by collaborator Elena Cattaneo, professor of pharmacy at the University of Milan. Like their 2004 findings in Huntington’s skin cells, the PA28-alpha and -beta subunit treatments did not increase proteasome activity in the Huntington-modeled striatal cells. Yet treatment with a different subunit, PA28-gamma, did work in these brain cells. “The findings show us that the system is specific and that simply increasing any proteolytic activity inside the cell may not work for the disease,” Isacson said.
Next, the proteasome-boosting PA28-gamma treatment was combined with exposure to toxic compounds, including glutamate agonists. By stressing the Huntington’s striatal cells with such compounds, the researchers saw that the PA28-gamma treatment protected against excitoxicity and other pathologically stressing events. The findings indicate that proteasome activation through gene therapy can provide an afflicted cell with a tool to combat its mutation.
Protein aggregates are a common pathological feature in many age-related neurodegenerative diseases, including beta-amyloid deposits in Alzheimer’s disease and alpha-synuclein buildup in Parkinson’s disease. It is unclear whether neurodegeneration in these conditions is due to protein aggregates or to other characteristic impairments in the sickly cells, including proteasome and mitochondrial dysfunction and the loss of trophic factors.