New compound targets mitochondrial damage in Parkinson’s models
Study links ClpP protection to improved motor and cognitive outcomes in mice
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- Parkinson’s disease involves toxic alpha-synuclein clumps and mitochondrial damage that drive neuron loss.
- The compound CS2 blocks a harmful alpha-synuclein–ClpP interaction, helping restore mitochondrial function.
- In mice, CS2 improved movement and cognition and helped preserve dopamine-producing neurons; further studies are planned.
Researchers at Case Western Reserve University in Cleveland, Ohio, developed a new compound that blocks a harmful interaction between the alpha-synuclein protein and a mitochondrial enzyme called ClpP. In a mouse model of Parkinson’s disease, the treatment helped preserve dopamine-producing brain cells and improved movement and cognitive performance.
The study found that when alpha-synuclein interacts with ClpP, it triggers the buildup of toxic protein clumps and mitochondrial damage — two processes closely linked to Parkinson’s disease. By blocking this interaction, the compound reduced toxic protein buildup and helped restore healthy mitochondria — the cell’s energy producers — and neurons.
“We’ve uncovered a harmful interaction between proteins that damages the brain’s cellular powerhouses, called mitochondria,” Xin Qi, PhD, the study’s senior author and professor at CWRU, said in a university news story. “More importantly, we’ve developed a targeted approach that can block this interaction and restore healthy brain cell function.”
The study, “Disrupting α-Synuclein–ClpP interaction restores mitochondrial function and attenuates neuropathology in Parkinson’s disease models,” was published in Molecular Neurodegeneration.
Parkinson’s involves the loss of dopamine-producing neurons
Parkinson’s is caused by the gradual loss of dopaminergic neurons — nerve cells that produce dopamine, a chemical messenger essential for movement. This cell loss occurs mainly in a brain region called the substantia nigra. Scientists believe that the buildup of toxic alpha-synuclein protein clumps and mitochondrial damage contribute to the damage and death of these neurons.
In this study, researchers used cell-based models and discovered that toxic alpha-synuclein interacts with the mitochondrial enzyme called ClpP. Under normal conditions, ClpP helps break down damaged or misfolded proteins and can limit alpha-synuclein clumping by helping maintain its normal structure.
This represents a fundamentally new approach to treating Parkinson’s disease. Instead of just treating the symptoms, we’re targeting one of the root causes of the disease itself.
This binding occurs through a specific region of alpha-synuclein, called the non-amyloid component, or NAC, a segment already known to promote protein clumping. When alpha-synuclein attaches to ClpP, it slows the enzyme’s activity, causing misfolded alpha-synuclein to build up inside mitochondria and interfere with the cell’s energy production.
The team designed CS2, a small protein that selectively binds the NAC region of alpha-synuclein, disrupting its interaction with ClpP. This helped restore ClpP levels and activity and reduced alpha-synuclein aggregation and mitochondrial stress across multiple models.
In mouse-derived cultured neurons treated with alpha-synuclein aggregates, CS2 reduced alpha-synuclein buildup and helped preserve neuronal structure and function. Similar effects were seen in dopaminergic neurons derived from Parkinson’s patients’ induced pluripotent stem cells (iPSCs) — adult cells that have been reprogrammed so they can develop into different cell types, including neurons.
Researchers tested CS2 in a Parkinson’s disease mouse model
Researchers tested CS2 in a Parkinson’s disease mouse model that exhibits hallmark features of the condition, including progressive alpha-synuclein accumulation, neuroinflammation (brain inflammation), and motor and cognitive deficits.
Sustained administration of CS2, delivered through subcutaneous (under-the-skin) osmotic mini pumps, improved mice’s motor abilities and cognitive function. The compound also restored ClpP levels and prevented ClpP-alpha-synuclein interactions, thereby reducing alpha-synuclein aggregation. CS2 treatment was also associated with preservation of dopaminergic neurons in the substantia nigra and reduced neuroinflammation.
“Taken together, these findings indicate that CS2 treatment attenuates [alpha-synuclein]-associated neuropathology and neuroinflammation in vivo by disrupting ClpP-[alpha-synuclein] interaction,” the researchers wrote.
“This represents a fundamentally new approach to treating Parkinson’s disease,” said Di Hu, PhD, the study’s first author. “Instead of just treating the symptoms, we’re targeting one of the root causes of the disease itself.”
Over the next five years, the team plans to optimize CS2 for potential human use, conduct additional safety and efficacy studies, and identify biomarkers to help advance the therapy toward clinical trials.
“One day, we hope to develop mitochondria-targeted therapies that will enable people to regain normal function and quality of life, transforming Parkinson’s from a crippling, progressive condition into a manageable or resolved one,” Qi added.
