CRISPR/Cas9’s Potential in Better Understanding and Treating Parkinson’s Focus of Review Study

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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In a recent review, scientists highlight the potential of gene editing technologies like CRISPR/Cas9 to not only understand the molecular mechanisms behind Parkinson’s disease, but also identify new targets for treatment.

The review study, “Interrogating Parkinson’s disease associated redox targets: Potential application of CRISPR editing,” was published in the journal Free Radical Biology and Medicine.

One of the hallmarks of PD is the loss of dopamine-producing neurons in the substantia nigra — a brain region involved in the control of voluntary movements, and one of the most affected in PD. This occurs due to the clustering of a protein called alpha-synuclein in structures commonly known as Lewy bodies inside neurons.

Parkinson’s is complex and multifactorial disease, with both genetic and environmental factors playing a role in either triggering or exacerbating the disease.

Genetic causes can explain 10% of all cases of PD —  called familial PD –, meaning that in the majority of the cases (sporadic PD) there is an interplay between genetics and environmental risk factors.

Researchers at Sechenov University in Russia and the University of Pittsburgh reviewed the role of metabolic pathways, especially problems with mitochondria — cells’ powerhouses — and iron accumulation, as well as mechanisms in cell death (called apoptosis and ferroptosis) in the development and progression of Parkinson’s disease.

These processes were discussed in the context of genome editing technologies, namely CRISPR/Cas9 — a technique that allows scientists to edit genomes, inserting or deleting DNA sequences, with precision, efficiency and flexibility.

“Empirical research has established many potential metabolic abnormalities that may represent the specific key mechanisms of PD pathogenesis. However, the diversity of these findings and the lack in understanding the connections between them slow down the progress in the development of specific treatments,” the researchers wrote. These abnormalities may be “[a]mong [the] many potentially important targets for CRISPR/Cas9 based research.”

“CRISPR is a promising technology, a strategy to find new effective treatments to neurodegenerative diseases,” Margarita Artyukhova, a student at the Institute for Regenerative Medicine at Sechenov and the study first author, said in a press release.

Mitochondria don’t work as they should in people with PD, resulting in shortages of cellular energy that cause neurons to fail and ultimately die, particularly dopamine-producing neurons. Faulty mitochondria are also linked to the abnormal production of reactive oxygen species, leading to oxidative stress — an imbalance between the production of free radicals and the ability of cells to detoxify them— that also damages cells over time.  

Because mitochondrial dysfunction is harmful, damaged mitochondria are usually eliminated (literally, consumed and expelled) in a process called mitophagy — an important cleansing process in which two genes, called PINK1 and PRKN, play crucial roles. Harmful changes in mitophagy regulation is linked with neurodegeneration in Parkinson’s.

Previous studies with animal models carrying mutations in the PINK1 and PRKN genes showed that these animals developed typical features of PD – mitochondrial dysfunction, muscle degeneration, and a marked loss of dopamine-producing neurons.

PINK1 codes for an enzyme that protects brain cells against oxidative stress, while PRKN codes for a protein called parkin. Both are essential for proper mitochondrial function and recycling by mitophagy. Mutations in both the PINK1 and PRKN gene have been linked with early-onset PD.

However, new research suggests that the role of PINK1 and PRKN in Parkinson’s could be more complex and involve other genes — like PARK7  (DJ-1), SNCA (alpha-synuclein) and FBXO7  — as well as a fat molecule called cardiolipin.

CRISPR/Cas9 genome editing technology may be used to help assess the role of different genetic players in Parkinson’s disease, and to look for unknown genes associated with disease progression and development. Moreover, this technology can help generate animal and cellular models that might help scientists decipher the role of certain proteins in Parkinson’s and discover potential new treatment targets.

Iron is another important metabolic cue in Parkinson’s. While it’s essential for normal physiological functions, excessive levels of iron can be toxic and lead to the death of dopamine-producing neurons in the substantia nigra.

Iron may also interact with dopamine, promoting the production of toxic molecules that damage mitochondria and cause alpha-synuclein buildup within neurons.

CRISPR/Cas9 technology can be used to help dissect the role of proteins involved in iron transport inside neurons, which in turn may aid in designing therapies to restore iron levels to normal in the context of Parkinson’s disease.

Finally, researchers summarized evidence related to the role of two cell death pathways — ferroptosis and apoptosis — in PD. Ferroptosis is an iron-dependent cell death mechanism by which iron changes fat (lipid) molecules, turning them toxic to neurons. This process has been implicated in cell death associated with degenerative diseases like Parkinson’s, and drugs that work to inhibit ferroptosis have shown an ability to halt neurodegeneration in animal models of the disease.

Apoptosis refers to a “programmed” cell death mechanism, as opposed to cell death caused by injury. Both apoptosis and ferroptosis speed the death of dopaminergic neurons.

CRISPR/Cas9 may help to pinpoint the key players in cell death that promote the loss of  dopaminergic neurons in Parkinson’s disease, while understanding the array of proteins that are involved in these processes.

“These insights into the mechanisms of PD pathology [disease mechanisms] may be used for the identification of new targets for therapeutic interventions and innovative approaches to genome editing, including CRISPR/Cas9,” the researchers wrote.

Genome editing technology is currently being used in clinical trials to treat patients with late-stage cancers and inherited blood disorders, Artyukhova notes in the release.

These “studies allow us to see vast potential of genome editing as a therapeutic strategy. It’s hard not to be thrilled and excited when you understand that progress of genome editing technologies can completely change our understanding of treatment of Parkinson’s disease and other neurodegenerative disorders,” she adds.