Research Targets Misfolded Alpha-synuclein

Scientists at Cognition Therapeutics have found that compounds that are able to dampen the activity of sigma-2 receptors — receptors that are part of a network that controls the destruction of misfolded proteins — are highly effective at preventing molecule trafficking defects driven by the presence of misfolded alpha-synuclein inside neurons.

According to researchers, the findings suggest these small molecule compounds may be used one day to fight neurodegeneration driven by the buildup of misfolded alpha-synuclein in patients with Parkinson’s disease and related neurological disorders.

“These data support the hypothesis that [sigma-2] receptor antagonists could represent a unique therapeutic approach to treating some of the underlying disease pathology [mechanisms] in Parkinson’s disease and potentially other related diseases like dementia with Lewy bodies,” Susan Catalano, PhD, said in a press release. Catalano is founder and chief science officer of Cognition, and senior author of the study. 

“We have plans to explore one or more compounds from our library of [sigma-2] receptor antagonists in models of Parkinson’s disease to better understand the role of [sigma-2] receptors in synucleinopathies,” Catalano said.

These findings were reported in the study “Sigma‐2 receptor antagonists rescue neuronal dysfunction induced by Parkinson’s patient brain‐derived α‐synuclein,” published in the Journal of Neuroscience Research.

Parkinson’s disease belongs to a class of neurodegenerative disorders known as synucleinopathies, in which the loss of nerve cells is mainly triggered by the buildup of misfolded alpha-synuclein, a protein that is particularly abundant in the brain, where it is thought to help control neuron function and communication.

In these disorders, alpha-synuclein misfolding is thought to be caused by cumulative cell damage resulting from a series of processes, including oxidative stress — a type of cellular damage caused by the accumulation of harmful oxidant molecules inside cells.

When misfolded, alpha-synuclein tends to aggregate and form protein clumps that have been shown to have a negative impact on several cellular functions, including molecule trafficking and autophagy — the process by which cells eliminate and recycle components they no longer need.

When these cellular processes start to malfunction, nerve cells become increasingly unable to clear alpha-synuclein aggregates, to the point where they reach toxic levels, causing cells to die.

Thus, agents that are able to interfere with the molecular and cellular mechanisms involved in the buildup of misfolded alpha-synuclein in nerve cells potentially may be used to halt or slow neurodegeneration, as well as ease disease symptoms.

To identify some of these potential therapeutic agents, Catalano and her colleagues screened several libraries of small molecule compounds that had been tested previously in clinical trials for their ability to restore defects in molecule trafficking and autophagy driven by the accumulation of alpha-synuclein aggregates. These screenings were preformed in protein preparations of alpha-synuclein that replicated the toxic effects of Parkinson’s patients’ brain‐derived alpha-synuclein.

After screening hundreds of compounds, investigators found that those able to bind and counteract the activity of sigma-2 receptors — receptors that are part of a network that controls several signaling cascades involved in cell damage response — were the most effective at restoring molecule trafficking and autophagy defects. These inhibitors, or antagonists, were effective at low concentrations and did not result in cytotoxicity at higher concentrations.

Although these findings were in agreement with studies describing the involvement of some components of these receptors on fatty molecule trafficking and autophagy, this was the first study to highlight the potential therapeutic value of small molecule antagonists on these receptors.

“These data support the hypothesis that targeting the sigma‐2 receptor complex with brain‐penetrant small molecule antagonists represents a tractable therapeutic approach to alleviating [alpha]‐synuclein‐induced pathology in [Parkinson’s disease] and other α‐synucleinopathies,” the researchers wrote.