Boost to natural change in alpha-synuclein may slow Parkinson's

20 Feb 2024, 13:00 by Patricia Inácio, PhD · Parkinson's News Today

A natural chemical modification — called O-GlcNAc — that occurs in specific building blocks of the alpha-synuclein protein can lessen its capacity to form toxic amyloid fibrils, a hallmark of Parkinson’s disease, a study shows.

“Taken together, we believe that these results have important implications for … the exploitation of O-GlcNAc in the treatment of PD [Parkinson’s disease] and other NDDs [neurodegenerative diseases],” its researchers wrote.

The study, “O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology,” was published in Nature Chemical Biology.

Alpha-synuclein misfolds in Parkinson’s, forming fibrous clumps

A common feature of diseases like Parkinson’s and Alzheimer’s is the accumulation of misfolded protein aggregates, or clumps, inside nerve cells (neurons) in the brain, the study and an accompanying press release noted.

Toxic aggregates of the alpha-synuclein protein are an associated cause of Parkinson’s, whereas amyloid-beta and tau protein clumps are linked with Alzheimer’s development. They all tend to form a specific type of insoluble, fibrous clumps called amyloid deposits or amyloid fibrils, which lead to nerve cell death.

Scientists led by those at the University of Southern California and the École Polytechnique Fédérale de Lausanne, in Switzerland, detailed a mechanism that promotes the formation of these amyloid fibrils.

They studied how post-translational modifications (PTMs) — changes made to proteins after they are produced by the cell — can influence the formation of amyloid fibrils in Parkinson’s disease.

Specifically, they focused on a particular PTM known as O-linked beta-N-acetylglucosamine or O-GlcNAc. In this modification, a single sugar molecule is added to specific amino acids — a protein’s building blocks — called serine or threonine. The addition ultimately alters the protein’s properties and function, and less of this modification has been linked with damaging processes, including protein clumping and nerve cell death.

O-GlcNAc of alpha-synuclein has been shown to slow amyloid aggregation and potentially protect neurons.

O-GlcNAc, a natural chemical modification, seen to slow amyloid fibril growth

Past research suggested that increasing the levels of O-GlcNAc could protect nerve cells by inhibiting the aggregation of amyloid fibrils to possibly slow disease progression.

“We and others have shown that O-GlcNAc on tau and [alpha-synuclein] can directly slow the kinetics of amyloid aggregation of these proteins in vitro in a site-specific fashion … increasing the levels of this modification with drugs may slow the progression of certain NDDs,” the researchers wrote.

In a further collaboration, the scientists developed chemical methods to produce modified alpha-synuclein fibrils in the lab.

In initial in vitro (in lab dish) work, alpha-synuclein with higher levels of O-GlcNAc still were capable of inducing the formation of fibrils, albeit to a lesser extent when compared with unmodified alpha-synuclein, which served as a control.

They then tested their properties in lab studies using mouse nerve cells found in the hippocampus, a brain region involved in memory and regulating emotions, and in disease animal models.

Results showed that alpha-synuclein fibrils with higher levels of O-GlcNAc modification had distinct properties. Specifically, these fibrils did not form clumps in neurons or trigger cell death.

Potential for way of protecting neurons from toxic protein aggregates

Notably, similar results were seen in in vivo [in a living organism] work, where the O-GlcNAc modified alpha-synuclein fibrils were injected into the brains of mice. When compared with unmodified alpha-synuclein, the O-GlcNAc fibrils resulted in markedly reduced signs of damage and aggregation in the substantia nigra — a brain region responsible for movement control and primarily affected in Parkinson’s disease.

Fewer aggregates also were detected in the animals’ amygdala, a brain region that controls emotional responses, and motor cortex, a region also is responsible for voluntary movement.

“Our results confirm that O-GlcNAc can force the formation of a [alpha-synuclein] amyloid strain with diminished pathogenicity in neurons and in vivo [in living mice]. This adds evidence for a model where O-GlcNAc may not only slow the aggregation of [alpha-synuclein], but could also protect against the progression of NDDs through multiple mechanisms,” the researchers wrote.

Enhancing the levels of O-GlcNAc modification with a therapy could prevent amyloid fibrils from spreading across different brain regions, halting Parkinson’s progression, they suggested.

“Our work on the O- GlcNac modification of [alpha-synuclein] sheds new light on the molecular determinants of the pathobiology of amyloid fibrils and provides new therapeutic targets for preventing amyloid growth and spreading at both early and late stages of disease development and progression,” the scientists wrote in a research briefing that accompanied their study.