Protein modifications found to be key influencers in neurodegenerative diseases

Neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, represent a significant health challenge, affecting more than 50 million people worldwide. A common feature of these diseases is the accumulation of misfolded protein aggregates in the brain, called amyloid fibrils, which disrupt normal cell function and ultimately lead to cell death.

In a new study, scientists led by Hilal Lashuel at EPFL and Matthew R. Pratt at USC have made significant progress in understanding how post-translational modifications (PTMs), i.e. i.e. the changes that occur to proteins after their synthesis in the cell, can influence the formation and pathogenicity of these amyloid fibrils.

Researchers studied the protein alpha-synuclein, linked to the formation of amyloid fibrils in Parkinson’s disease. The researchers looked at a specific modification the protein undergoes, technically known as “O-linked β-N-acetylglucosamine” or O-GlcNAc for short.

O-GlcNAc is a kind of modification that adds a single sugar molecule to specific serine or threonine residues in the protein, thereby changing its function and properties. It has been linked to several biological processes, including protein aggregation and neurodegeneration. This modification, particularly on alpha-synuclein, has been shown to slow amyloid aggregation and potentially protect neurons.

Previous studies by Pratt and Lashuel’s groups suggested that increased O-GlcNAc modification may have therapeutic potential in the early stages of neurodegenerative disease, by altering the properties of protein aggregates to prevent their seeding and spread throughout the brain, potentially slowing disease progression.

Based on this, the team used innovative chemical methods to produce modified alpha-synuclein fibrils, in collaboration with Virginia Lee’s group at the University of Pennsylvania. They also used cellular and animal models to study how O-GlcNAc affects the pathogenic properties of alpha-synuclein and worked with Lorena Saelices’ group at UT Southwestern Medical Center to observe the modified fibrils using cryoelectron microscopy.

The study showed that increased modification produced fibrils with distinct structural and biochemical characteristics. These fibrils result in a strain of amyloid fibrils with a significantly reduced ability to seed aggregation in neurons and animal models of Parkinson’s disease. Interestingly, this strain of fibrils can cause aggregation in vitro, but not in neurons or in live mice.

“Our results show that this environment in the cell plays an important role in determining the pathogenicity of this protein,” explains Anne-Laure Mahul, one of the co-first authors of the study.

The study suggests that modifications such as O-GlcNAc may play a role in modulating the pathogenicity of alpha-synuclein, opening new avenues of research and potential treatments. For example, targeting the process of O-GlcNAc modification could lead to therapies that modify the progression of Parkinson’s disease by influencing the ability of pathogenic alpha-synuclein species to spread to different regions of the brain.

In a related research paper by Nature write the authors: “(N)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 to prevent the growth and spread of amyloid both in the early stage. and the later stages of disease development and progression.

The research is published in the journal Nature Chemical Biology.