Misfolded Protein Aggregates in Neurodegenerative Diseases

Researchers at the University of Alberta and the National Institute for Nanotechnology in Canada recently reported new insights into the misfolding process of proteins from a normal structure to a disease state characteristic of degenerative disorders. The study entitled “Protein misfolding occurs by slow diffusion across multiple barriers in a rough energy landscape” was published in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).

Neurodegenerative disorders like amyotrophic lateral sclerosis (ALS), Alzheimer’s and Parkinson’s disease are caused by protein misfolding and aggregation, although the protein component and affected brain region may differ. The timescale linked to the protein dynamics during conformational transitions is set by the intrachain diffusion coefficient (D), a coefficient that determines the transition kinetics and the microscopic properties of the interactions in the folding process. D has never been determined for misfolded and aggregated proteins.

“This is the big mystery we’re trying to solve,” said the study’s senior author Dr. Michael Woodside in a news release. “We want to understand the physics of the conversion from ‘good’ proteins to ‘bad.’”

The team used single-molecule force spectroscopy to determine D in the misfolding of a protein called PrP (prion protein). Prions are abnormal, pathogenic agents that are able to induce anomalous folding of specific cellular proteins. Researchers tested the interaction between two PrP molecules, analyzed misfolding processes, the formation of stable incorrect structures and reconstructed the energy landscape regarding the formation of aggregates. Using sensitive laser tweezers, the team manipulated the proteins and determined their microscopic motions as they changed shape. They found that D was 1,000-fold slower for misfolding processes than for native folding, and that this slow diffusion led to longer transit times which allowed for the first time the analysis of transition paths.

The research team believes that their work offers new insights into the microscopic mechanisms behind protein misfolding. “Our work is best viewed as just one step in solving a big mystery that still endures almost 20 years after the Nobel Prize was awarded for the prion hypothesis.” concluded Dr. Woodside. Understanding the physical principles underlying the generation of misfolded protein aggregates may lead to new therapeutic strategies against degenerative diseases including ALS.

ALS is a progressive neurodegenerative disease characterized by the gradual degeneration and atrophy of motor neurons in the brain and spinal cord that are responsible for controlling essential voluntary muscles, such as the ones related to movement, speaking, eating, and even breathing. In ALS, proteins like TDP-43 accumulate in the neurons becoming toxic. It is estimated that more than 300,000 Americans suffer from the disease for which there is currently no cure.