Molecule Shows Potential to Stop Toxic Protein Clumping in Lab Study

A high throughput cell-based study looked at thousands of potential candidates for treating Parkinson’s and potentially stopping disease progression, noting a particularly promising candidate, designated A-443654.

Yedida Y Bogachkov PhD avatar

by Yedida Y Bogachkov PhD |

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A molecule showed a potential in early studies to slow the production of alpha-synuclein, a protein that forms large toxic aggregates in the brains of  people with Parkinson’s disease, a research team reported.

Called A-443654, the molecule lowered to normal levels the protein’s production in nerve cells derived from a Parkinson’s patient and another cell type, suggesting it may be an essential step in “developing an effective therapeutic” for this and similar disorders marked by alpha-synuclein clumping, the researchers wrote.

Their study, “The AKT modulator A-443654 reduces α-synuclein expression and normalizes ER stress and autophagy,” was published in the Journal of Biological Chemistry.

In healthy brains, alpha-synuclein is thought to play a role in how nerve cells communicate with one another. However, in those affected by Parkinson’s, alpha-synuclein sticks together to form clumps within neurons (nerve cells) that damages and can kill these cells.

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“Most cases of Parkinson’s disease are characterized by an overabundance of alpha-synuclein. The prevailing thought is that if you lower its overall abundance, this would be therapeutic,” Daniel Scoles, PhD, an associate professor of neurology at the University of Utah and the study’s lead researcher, said in a press release.

Researchers led by those at Utah wanted to identify molecules that might lower alpha-synuclein levels.

To do this quickly and efficiently, they used gene editing tools to insert a gene that encodes a light-producing protein, isolated from fireflies, into human cells grown in the lab. This gene was positioned so that it would be “turned on” whenever the gene that encodes for alpha-synuclein was active, causing the cells to glow, and to dim as the alpha-synuclein gene became less active.

Using high-throughput screening, they proceeded to test 155,885 different compounds in fibroblasts (cells found in connective tissue) and in dopaminergic neurons — those that secrete dopamine and are gradually lost in Parkinson’s — derived from a patient who carried a mutation in the SNCA gene, which is responsible for alpha-synuclein production.

A-443654 emerged as the candidate best able to block alpha-synuclein production from this work. (High-throughput screening is the use of automated equipment to rapidly test thousands to millions of samples, allowing a biochemical or cellular event to be reproduced and rapidly tested several hundreds of thousands of times.)

When the two groups of cells were exposed in the lab to A-443654, alpha-synuclein levels were normalized, the team reported.

Researchers found that this particular molecule decreased the SNCA gene’s activity in both types of cells, and lowered the amount of alpha-synuclein protein that this gene worked to produce.

A-443654 also seemed to reduce the stress that alpha-synuclein aggregates exert on the systems neurons use to clear damaged or unwanted proteins (a process called autophagy). This indicates that A-443654 may allow nerve cells to break down clumps of alpha-synuclein that have already formed.

“We can stop production, but we also need to degrade what’s already in aggregate. The more aggregated this is, the more toxic it becomes,” said Mandi Gandelman, PhD, a researcher in the university’s neurology department and a study author.

“This study adds to a body of research focusing on modulating [alpha]-synuclein expression to treat PD [Parkinson’s disease], presenting A-443654 as an additional lead toward restoring cellular functions impaired in PD and related [alpha]-synucleinopathies,” the researchers wrote.

“The pharmacology of A-443654 on PD pathways highlights its potential as a preventative of the multifactorial cascades that are responsible for the death of dopaminergic neurons,” they added.

More work is needed to assess whether A-443654 can be developed into a treatment for Parkinson’s and other diseases involving alpha-synuclein aggregates, like Lewy body dementia.

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