In Cellular Studies, Gene Editing Rescues Parkinson's Disease Phenotypes

Ornit Chiba-Falek, Ph.D.
GCB News

In Cellular Studies, Gene Editing Rescues Parkinson's Disease Phenotypes

By Jamie Talan -- Neurology Today

In a gene editing experiment involving human induced pluripotent stem cells from a patient with a familial form of Parkinson's disease, turning up DNA methylation led to a downregulation of SNCA messenger-RNA and reduced alpha-synuclein protein levels by about a third — sufficient to reverse the mitochondrial dysfunction, cellular vulnerability, and neuronal death that are part of the disease's pathological phenotype.

Ornit Chiba-Falek and team used gene editing techniques to target DNA methylation on a region of a gene implicated in Parkinson's disease (PD) — SNCA — and reduced levels of alpha-synuclein transcript and protein.

Elevated levels of wild-type alpha-synuclein are thought to drive dopaminergic neuronal loss and in turn susceptibility to PD. The researchers were intrigued by earlier studies that had shown that the DNA-methylation state within a region located in intron 1 of SNCA gene affects alpha-synuclein expression. Others in the field have reported disease-related changes in DNA methylation in this region of SNCA intron 1, they said.

In the current experiment, turning up DNA methylation led to a downregulation of SNCA messenger-RNA and reduced alpha-synuclein protein levels by about a third — sufficient to reverse the mitochondrial dysfunction, cellular vulnerability, and neuronal death that are part of PD's pathological phenotype.

DNA methylation is an epigenetic phenomenon, said Ornit Chiba-Falek, Ph.D., associate professor of neurology at Duke and senior author of the study in the November 7, 2018, issue of Molecular Therapy. “It does not alter the DNA sequence but is added to the DNA to regulate the genome activity, and it controls transcription and gene expression.

“It is important to maintain physiologically normal levels of alpha-synuclein,” said Dr. Chiba-Falek. “This epigenome editing technique rescued the Parkinson's phenotypes at a cellular level,” she said.

The researchers are planning to test this approach in a rat model of PD. “This approach would be highly attractive for developing ‘smart drugs’ as disease-modifying therapies and preventative interventions for PD, Alzheimer's disease, and other neurological diseases and pathologies associated with dysregulation of gene expression,” Dr. Chiba-Falek added.

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