Cutting out a portion of or removing a gene linked to Parkinson’s disease protects against the formation of toxic protein clumps within brain cells, scientists have found.
This discovery has the potential to significantly affect the development of next-generation cell-based therapies, which involve injecting healthy cells into brain regions already affected by the disease. Researchers believe the approach may help relieve motor symptoms such as tremor and balance issues.
Findings were published in the study, “Engineering synucleinopathy-resistant human dopaminergic neurons by CRISPR-mediated deletion of the SNCA gene,” in the European Journal of Neuroscience. The work was funded by the U.K. Centre for Mammalian Synthetic Biology, UCB, and The Cure Parkinson’s Trust.
Mutations in the SNCA gene have been found to cause Parkinson’s, a condition characterized by the selective death of midbrain dopamine-producing neurons due to clustering of a protein called alpha-synuclein, also known as Lewy bodies.
Transplantation of dopamine-producing neurons has proved useful in disease management because it can reinnervate Parkinson’s-affected brain regions, restore dopamine levels, and provide symptom relief.
Clinical studies on the transplant of fetal mesencephalic (meaning “of or relating to the midbrain”) tissue into the striatum — a critical area of the brain involved in Parkinson’s — have shown that although some patients saw their motor symptoms improved, others had transplant-induced dyskinesias — abnormal, uncontrolled, and involuntary movement.
Importantly, transplanted tissue (grafts) older than 10 years developed Lewy bodies, which reduced the symptomatic benefit to the patient.
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“These clinical observations highlight the need for cell therapies that are resistant to the formation of Lewy bodies. … Such disease-resistant cells will be particularly important for patients with young-onset Parkinson’s or genetic forms of the condition with substantial alpha-synuclein burden,” the researchers wrote.
The team used a gene editing tool known as CRISPR-Cas9. This technique allows scientists to edit parts of the genome by removing, adding, or altering specific sections of the DNA sequence.
Using stem cells, researchers created two distinct cell lines: one with snipped-out portions of the SNCA gene and another without the SNCA gene.
These stem cells were then transformed into dopamine-producing neurons and treated with a chemical agent (recombinant alpha-synuclein pre-formed fibrils) to induce the formation of Parkinson’s-related Lewy bodies.
The team reported that wild-type neurons, or unedited brain cells, were fully susceptible to the formation of toxic aggregates, while engineered cells were significantly resistant to Lewy body formation.
“We know that Parkinson’s disease spreads from neuron [to] neuron, invading healthy cells. This could essentially put a shelf life on the potential of cell replacement therapy. Our exciting discovery has the potential to considerably improve these emerging treatments,” Tilo Kunath, PhD, group leader at the Medical Research Council’s Centre for Regenerative Medicine, University of Edinburgh, and senior author of the study, said in a press release.
By finding a way to “shield” cells from Parkinson’s molecular changes, scientists may have opened the door to the development of cell therapies capable of diverting time’s negative effect on transplanted tissue.