Blocking synuclein nitrase eases paralysis in mouse study

Suppressing the enzyme could have therapeutic potential

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A mouse is seen an an oversized human hand, flanked by vials of serum.

Blocking the activity of the synuclein nitrase enzyme reduced the levels of toxic clumps of the alpha-synuclein protein and lessened paralysis in mouse models of Parkinson’s disease, according to new data from Nitrase Therapeutics.

Formation of toxic aggregates of alpha-synuclein is a hallmark of Parkinson’s and “has been identified as a key driver of … Parkinson’s disease,” Irene Griswold-Prenner, PhD, Nitrase’s founder and chief scientific officer, said in a press release.

These findings suggest that suppressing synuclein nitrase could be a potential therapeutic approach for Parkinson’s.

“We are working to develop a small molecule therapeutic targeting Synuclein Nitrase that has potential to slow progression of Parkinson’s disease,” Griswold-Prenner added.

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Scientists at Nitrase shared the findings at the AD/PD 2023-International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders, being held March 28-April 1 in Gothenburg, Sweden and virtually.

The presentation was titled “Alpha Synuclein Nitration and Aggregation in Neurons is Controlled by the Novel Enzyme Synuclein Nitrase” (abstract #412).

Parkinson’s is characterized by the death and dysfunction of neurons in the brain that produce a major chemical messenger called dopamine. This neurodegeneration is thought to be driven by the formation of toxic alpha-synuclein aggregates inside of brain cells.

Synuclein nitrase is an enzyme discovered by scientists at Nitrase that performs nitration of the alpha-synuclein protein. Nitration is a type of biochemical modification of proteins that is linked to cellular stress and can change that protein’s structure, function, and localization.

Previous preclinical data showed that suppressing synuclein nitrase normalized the electrical activity of lab-grown, patient-derived dopamine-producing neurons by reducing alpha-synuclein clumps.

Three mouse models

Now, the researchers explored the role of the synuclein nitrase enzyme in both cellular and mouse models of Parkinson’s. Three types of models were used: one based on exposure to methamphetamine, one exposed to pre-formed fibrils, and the other based on genetic modification to produce a toxic form of alpha-synuclein.

Methamphetamine can cause damage to the same brain regions that are affected in Parkinson’s, and data suggest that people who use methamphetamine recreationally are at increased risk of Parkinson’s. Pre-formed fibrils are the longer and insoluble clumps of alpha-synuclein that are known to promote further aggregation.

Results showed that the genetic deletion of synuclein nitrase prevented alpha-synuclein nitration and reduced protein aggregation in both cellular and animal models. Treatment with NB001, a small molecule that blocks more than one type of nitrase, also reduced alpha-synuclein nitration in healthy mice.

Importantly, genetically deleting synuclein nitrase lessened motor impairment, particularly paralysis, in a mouse model of Parkinson’s disease.

“We have discovered a novel enzyme called Synuclein Nitrase, and these data suggest that alpha synuclein nitration and aggregation in neurons is controlled by this novel enzyme,” Griswold-Prenner said. “Strikingly, knocking out Synuclein Nitrase resulted in reduced paralysis in mouse models of Parkinson’s disease.”

These findings suggest that synuclein nitrase “impacts three key hallmarks of Parkinson’s disease – [alpha-synuclein] nitration, [alpha-synuclein] aggregation, and motor dysfunction,” Nitrase stated in the release.

“Development of a Synuclein Nitrase therapeutic could result in significant disease-modification of Parkinson’s disease,” the scientists wrote in their abstract.

Nitrase previously received two awards from the Michael J. Fox Foundation for Parkinson’s Research to further explore synuclein nitrase’s potential as a biomarker and therapeutic target of Parkinson’s.

The company also has entered into a collaboration with HitGen to develop  new therapies that can block the activity of synuclein nitrase and related molecules.