Murray, Kevin A., et al.

“Small Molecules Disaggregate Alpha-Synuclein and Prevent

Seeding from Patient Brain-Derived Fibrils.” Proceedings of the National Academy of
Sciences, vol. 120, no. 7, 9 Feb. 2023, https://doi.org/10.1073/pnas.2217835120.
Accessed 5 Mar. 2023.

Parkinson's disease (PD) and other similar synucleinopathies which include DLB and
multiple system atrophy typically involve amyloid aggregation of alpha-synuclein in the
brain as a pathogenesis (MSA). There are no treatments for synucleinopathies that alter the
course of the disease. One of the main therapeutic targets for the treatment of these disorders
is alpha-synuclein aggregation.

Two tiny compounds that can break up already-formed alpha-synuclein fibrils were
discovered in this study. The substances, known as CNS-11 and CNS-11g, inhibit
intracellular seeded aggregation of alpha-synuclein fibrils, disaggregate recombinant alpha-
synuclein fibrils in vitro, and lessen the cytotoxicity of alpha-synuclein fibrils in neuronal
cells. Also, it was shown that both substances deconstruct fibrils taken from the brains of
MSA patients and stop their intracellular seeding. Also, they lessen C. elegans' in vivo alpha-
synuclein aggregation. Both substances reach mouse brain tissue. The N terminus of the fibril
core may be affected by the chemicals' disaggregating activities, according to a computer
model based on molecular dynamics. It was said that these substances seem to be promising
therapeutic leads for treating synucleinopathies by targeting alpha-synuclein.

One might ask what the significance of this study is. The accumulation of alpha-synuclein
into fibrils within the brain is linked to PD and MSA. The progression of these disorders
might be slowed down or stopped by disaggregation of these fibrils. The discovered two tiny
compounds that break down alpha-synuclein prepared fibrils in a test tube, including fibrils
from postmortem patient brains, as a first step toward testing this theory. These two
substances could be developed into treatments for PD and MSA since they enter the mouse
brain and decrease alpha-synuclein aggregation in the worm C. elegans.

The disassembly of alpha-synuclein by two drugs, CNS-11 and CNS-11g, was established in
this study using both in vitro and in vivo models. Additionally, it was demonstrated that these
substances can penetrate living mouse brain tissue and are effective against alpha-synuclein
fibrils that have been taken directly from patient brain tissue. These early findings show the
promise of these compounds as leads for future medication development toward the treatment
of synucleinopathies, while more research will be required to confirm their therapeutic
efficacy. The physicochemical characteristics of a drug-like substance and the compounds'
effects on tau aggregates suggest that CNS-11 and its related analogs may one day be used to
treat other disorders characterized by abnormal protein aggregation.

According to the calculations given, there are limitations; interactions with charged side
chains and hydrogen bonds with amide backbone groups appear to be the main driving forces
for the binding of either molecule to the fibril. To completely determine their specific mode
of action, additional structural and biochemical research will be required additionally in the
future. Many more distinct polymorphic structures of alpha-synuclein were identified by
published research so far. A conserved protein fold that is found in both the recombinant and
MSA folds of the alpha-synuclein fibril is common to several of these structures. Because the
recombinant fibril structure has this conserved core region, researchers tried to use it as a
generic model for our MD simulations.