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Parkinson's disease (PD) is a devastating neurodegenerative disorder. While the exact pathogenic mechanisms underlying PD remain complex and multifactorial, emerging evidence points to the critical role of poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation in driving neuronal cell death and disease progression. At Alfa Cytology, we provide PARP inhibitor development services for the PD therapy.
While the precise etiology of PD remains complex and multifactorial, a growing body of evidence has implicated the central role of pathogenic α-synuclein (α-syn) aggregation and propagation in driving neurodegeneration. Emerging research suggests that the aberrant activation of poly(ADP-ribose) polymerase-1 (PARP1) is a critical pathogenic mechanism underlying α-syn-mediated neuronal death in Parkinson's disease. PARP1 is a nuclear enzyme that plays a crucial role in the cellular response to DNA damage and other forms of cellular stress.
Fig. 1 PARP1 as a Therapeutic Target for α-Synucleinopathies. (Olsen A. L., et al. 2019)
Numerous studies have demonstrated the direct link between PARP1 hyperactivation and the toxic effects of pathogenic α-syn species, including oligomers and pre-formed fibrils (PFFs):
α-Syn Accumulation Activates PARP1
The accumulation of misfolded α-syn can directly activate PARP1, leading to the depletion of cellular energy stores, mitochondrial dysfunction, and ultimately, neuronal death.
PARP1 Inhibition Mitigates α-Syn Pathology
Pharmacological inhibition of PARP1 has been shown to attenuate the detrimental effects of α-syn aggregates, including the reduction of phosphorylated α-syn levels and the preservation of NAD+ homeostasis.
PARP1 Inhibitors Confer Neuroprotection
In preclinical models of Parkinson's disease, PARP1 inhibitors have demonstrated the ability to slow the progression of motor deficits and neurodegeneration, highlighting their potential as disease-modifying therapeutic agents.
Given the central role of PARP1 hyperactivation in driving α-syn-mediated neurodegeneration, targeting this enzyme has emerged as a promising therapeutic strategy for Parkinson's disease and related α-synucleinopathies. Studies have shown that rucaparib exhibits significant effects on preventing dopaminergic neuronal degeneration in AIMP2 transgenic mice. Ongoing research efforts are focused on developing potent and selective PARP1 inhibitors with the goal of advancing novel, disease-modifying therapies for Parkinson's disease.
| Experimental Model | Disease Modelled | PARP Inhibitor | Effects |
| Dopaminergic neuron loss in AIMP2 transgenic mice | Parkinson disease | Rucaparib | Prevention of degeneration of dopaminergic neurons |
Alfa Cytology offers a comprehensive suite of services to support the development of PARP inhibitor-based therapies for stroke recovery. Our team of experts is dedicated to providing high-quality, data-driven solutions that accelerate the progress of our clients' research and development efforts.
Modeling Services
At Alfa Cytology, we are committed to advancing the development of PARP1 inhibitors as a transformative therapeutic approach for Parkinson's disease and related α-synucleinopathies. Our team of scientists is dedicated to collaborating with pharmaceutical and biotechnology partners to accelerate the clinical translation of this promising strategy. To learn more about our PARP1 inhibitor research services or to discuss a potential partnership, please don't hesitate to contact us.
Reference
For research use only. Not intended for any clinical use.