Research Offers Clues Into Destruction of Brain Proteins in Parkinson

New international research probed different forms of proteins found in the brain to try and determine which one may be the most promising for future therapeutic interventions for Parkinson disease (PD).

The researchers compared different forms of α-synuclein and found that β-sheet fibrillar forms may represent a promising target, because it is the form that is the most destructive to neurons.

While the role of α-synuclein in neurodegeneration and in creating PD symptoms is an area of active research, it is generally understood that α-synuclein clumps together and damages neurons. Those tangles progressively spread throughout the brain.

In a statement from the University of Alabama, which led the study, researchers said that β-sheet fibrillar fragments make overlapping sheets of the protein, which develop into long filaments and then break into even smaller fragmented pieces. Those smaller pieces are able to attack and destroy normal brain protein, they said.

As the damage unfolds, there is reduction in the chemical messenger dopamine, which coordinates movement. Loss of dopamine is well-associated with PD.

In a mouse study, the researchers found that injecting them with β-sheet oligomers caused a slight but significant loss of dopamine neurons in a section of the brain called the substantia nigra pars compacta (SNc), but it did not create clumping or cause a loss of motor function. However, injecting them with short fibrils did create clumping, motor function loss, and loss of dopamine.

"Designing therapeutic strategies to halt the progression and spread of synucleinopathies such as PD requires characterization of the specific forms of α-synuclein that are responsible for given phenotypes, including the formation of inclusions in multiple brain areas, the loss of dopamine terminals, the reduction in the numbers of neurons in the SNc, and the loss of normal motor behavior," the researchers wrote. "In this study, we have used a combination of biophysical, biochemical, and behavioral assays to demonstrate that small aggregates composed primarily of small fragments of α-synuclein fibrils are able to induce typical features of PD when injected into the brains of healthy mice."

“We’ve long known that the aggregation or clumping of alpha-synuclein plays an important role in diseases such as Parkinson’s,” said Laura Volpicelli-Daley, PhD, assistant professor in the Department of Neurology in the School of Medicine. “We think that, by preventing alpha-synuclein from forming aggregates, we can prevent progression of the disease. All this suggests that beta-sheet fibrillar fragments specifically should be a target for development of therapeutic strategies, such as immunotherapy, that might reduce the formation and propagation of this form of alpha-synuclein,” Volpicelli-Daley said. “This strategy may work to slow or stop the progression of Parkinson’s and other disorders that involve alpha-synuclein, such as Lewy body dementia.”

Reference

Froula JM, Castellana-Cruz, M, Anabtawi NM, et al. Defining α-synuclein species responsible for Parkinson's disease phenotypes in mice [published online July 5, 2019]. J Biol Chem. doi: 10.1074/jbc.RA119.007743.