VARI finds potential ‘guardian’ against neurodegeneration


Van Andel Institute, or VAI, in downtown Grand Rapids is a biomedical research and science education nonprofit established by Jay and Betty Van Andel in 1996.

Scientists at Van Andel Research Institute might have found a “guardian” against neurodegeneration that could impact diseases like Parkinson’s.

Stopping disruptions in cellular "trash removal" brought on by errors in molecular marks on DNA may guard against neurodegenerative diseases, according to VARI.

VARI professor Gerd Pfeifer and his team’s novel findings implicate certain epigenetic modifications — marks on the DNA that affect gene regulation without changing the genetic code — in the development of some neurodegenerative diseases.

His team has demonstrated how a protein called Tet3FL removes molecules called methyl groups from specific genes, keeping them active and the "trash removal" processes working.

Without these vital “housekeeping functions,” abnormal proteins and other cellular waste can accumulate and cause damage.

"When we looked at the data, Tet3FL was surprisingly specific. We found a relatively small number of genes associated with it, the majority of which are part of the lysosomal and autophagic pathways," Pfeifer said.

"These pathways are responsible for clearing out old and damaged proteins and other cellular components, and have been previously linked to neurodegenerative diseases. Importantly, mutations in one of these genes, GBA, are recognized as the strongest genetic risk factors for developing Parkinson's.”

Pfeifer said knowing how these genes are regulated, especially genes like GBA, could help scientists develop novel treatments for neurodegenerative diseases.

Brain cells are largely non-dividing, meaning a person has essentially the same set for their entire life while other cells, like skin cells, turn over frequently.

When epigenetic marks, such as methyl groups, are inappropriately added to DNA in cells that frequently divide, the negative effect is usually diluted out by removal of these marks during cellular division, Pfeifer said.

In non-dividing cells (a group that includes most nerve cells in the brain), however, the effects of a gene being switched off due to improper methylation can be more profound.

Pfeifer said this is where Tet3FL comes in — it stays close to a specific site on particular genes and removes methyl groups as needed, maintaining the functionality of those genes and, in effect, potentially acting as a "guardian" against neurodegenerative diseases.

Pfeifer plans to collaborate with other scientists at VARI, including renowned neuroscientist and Parkinson's expert Patrik Brundin, Ph.D., to further explore how Tet3FL may provide protection against neurodegenerative diseases.

"These findings open a new avenue to explore potential new ways to prevent and treat diseases like Parkinson's," Brundin said.

The study was published in “Cell Reports” with VARI's Seung-Gi Jin, Ph.D., as first author. It was conducted in collaboration with VARI’s Piroska Szabó, Ph.D., and scientists at Beckman Research Institute of the City of Hope; University of California, Riverside; and the State Key Laboratory of Molecular Biology at the Chinese Academy of Sciences.

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