Researchers have discovered a factor that controls the accumulation of both alpha-synuclein and tau, two proteins that drive neurodegeneration in Parkinson’s and Alzheimer’s diseases.
The findings bring not only a new understanding of how the two conditions may be linked, but also offer possibilities for the development of new treatment approaches.
The study, “TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau,” was published in the journal eLife.
Physicians of Parkinson’s disease patients have noted that some patients also develop dementia. Research has shown that in these patients’ brains, the typical Alzheimer’s protein tau is present, in addition to the typical Parkinsonian clumps of alpha-synuclein protein. Likewise, some patients with Alzheimer’s have alpha-synuclein littering their brains.
These facts inspired the research team at Baylor College of Medicine and Texas Children’s Hospital, to embark on a search for possible factors that could control the accumulation of both alpha-synuclein and tau.
Their search started out on a genetic level. Using both human cells and fruit flies, they screened for genes that could impact the levels of each protein separately. Then they compared the results for alpha-synuclein and tau.
Although several genes were involved in controlling each protein, only one could impact the levels of both alpha-synuclein and tau. The factor is called TRIM28, and researchers have known about its existence from studies of embryonic development.
“Here we have discovered that it can also regulate proteins that contribute to the development of Alzheimer’s and Parkinson’s disease,” Huda Zoghbi, MD, professor of molecular and human genetics, and of pediatrics, neurology and developmental neuroscience, at Baylor, said in a press release. Zoghbi is the study’s senior author.
Having identified the gene, the team continued with experiments in both mice and lab-grown cells to study the effects of TRIM28 on the two proteins. When halving the amount of TRIM28, the levels of alpha-synuclein and tau decreased, too, as was the damage to the cells.
They then tried the reverse approach and increased TRIM28 in two types of mice: one in which alpha-synuclein accumulated more than in normal mice, and another where tau tended to aggregate.
“We observed that overexpressing TRIM28 accelerated the accumulation of the proteins in the respective animal models,” Maxime Rousseaux, PhD, the first author of the study, explained.
The team, however, did not stop with these experiments. Working together with colleagues at Johns Hopkins University School of Medicine, they discovered that in the brains of deceased humans who died from Parkinson’s disease or similar conditions, TRIM28 also could be linked to the accumulation of alpha-synuclein and tau.
“Our work shows that by reducing the activity of TRIM28 we can clearly reduce the accumulation of tau and alpha-synuclein in fruit flies and mouse models of the disease,” said Zoghbi, who also is director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital.
“These results encourage us to consider the possibility of developing drugs that could reduce the levels of TRIM28 to help prevent the development of Alzheimer’s, Parkinson’s and related diseases,” she said.