Lab-made small molecule may help slow brain disease progression
SK-129 aims to prevent formation of toxic protein clumps
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- Parkinson's and related diseases involve toxic alpha-synuclein protein clumps.
- SK-129, a lab-made molecule, reduced these toxic protein clumps and their spread.
- It crossed the blood-brain barrier, showing promise for slowing disease progression.
A small, lab-made molecule called SK-129 reduced the formation of toxic clumps of the alpha-synuclein protein, a hallmark of Parkinson’s disease, a study found.
SK-129 was able to cross the blood-brain barrier – a semipermeable membrane that protects the brain and central nervous system – and prevent damage caused by these toxic clumps, as well as their spread across the brain.
The findings may also be relevant to other Parkinson’s-like diseases characterized by abnormal clumping of the protein alpha-synuclein, including Lewy body dementia and multiple system atrophy.
“This is an important step toward developing treatments that target the root cause of these diseases,” Mazin Magzoub, PhD, associate professor of biology at NYU Abu Dhabi and a co-lead author on the study, said in a New York University press release. “Instead of only treating symptoms, we are working toward slowing or stopping the disease itself.”
The study, “Foldamers rescue synucleinopathy phenotypes in multiple in vitro and in vivo models,” was published in the journal Science Translational Medicine.
Misfolded protein forms toxic clusters
Parkinson’s disease is caused by the progressive loss of dopamine-producing neurons, a type of nerve cell important for movement control.
A hallmark of Parkinson’s and related disorders, collectively known as synucleinopathies, is the formation of toxic clumps of the protein alpha-synuclein in brain cells. In healthy neurons, alpha-synuclein normally exists in a monomeric (single-molecule) form and is involved in nerve cell communication.
But when the protein misfolds, it can assemble into small toxic clusters called oligomers, which then form larger aggregates that make up Lewy bodies, a key disease-causing feature of Parkinson’s. These clumps contribute to cell death and spread in a prion-like manner, meaning aggregates in one brain region may trigger more misfolding in nearby regions.
That means preventing alpha-synuclein from clumping and spreading is seen as a promising strategy for treating synucleinopathies.
Researchers at NYU Abu Dhabi and the University of Denver focused on the potential of foldamers, lab-made molecules designed to mimic features of natural proteins. Specifically, they investigated SK-129, a foldamer designed to inhibit alpha-synuclein aggregation.
In lab tests, they found that SK-129 blocked alpha-synuclein from clumping together and reduced disease-related effects across several lab models, including nerve cells derived from human induced pluripotent stem cells (iPSCs) and animal models such as the worm Caenorhabditis elegans and mice. iPSCs are cells that can generate almost any type of cell in the body.
The compound showed a strong ability to bind toxic alpha-synuclein oligomers — small, harmful protein clusters believed to play a key role in disease — with about six times greater affinity than it showed for the protein’s normal, healthy monomeric form. That selectivity could validate alpha-synuclein oligomers “as a therapeutic target,” the researchers wrote.
The scientists also found that SK-129 crossed the blood-brain barrier, which typically prevents certain drugs from reaching the brain.
In a mouse model carrying the A53T mutant form of human alpha-synuclein, which is known to form toxic clumps more readily in the brain, the compound increased the mice’s survival without signs of toxicity.
Additional experiments showed that SK-129 blocked alpha-synuclein aggregation triggered by exosomes derived from C. elegans or from Parkinson’s patients. Exosomes are tiny vesicles released by neurons and other cells, and have been implicated in the transmission of misfolded proteins, including alpha-synuclein, in people with Parkinson’s.
The molecule also inhibited the co-aggregation of alpha-synuclein and another protein called tau, a disease-causing feature associated with Lewy body dementia, in both cellular and mouse models.
While SK-129 needs further testing before it can reach clinical trials or patients, the researchers said the results point to its potential as a therapeutic agent for Parkinson’s and Lewy body dementia.
