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Assessing the Neuroprotective Factor REST/NRSF as a Therapeutic Target for Parkinson’s Disease

Study Rationale: Evidence suggests that a regulatory factor called REST (also known as NRSF) could promote the survival of neurons in neurodegenerative conditions. Studies have shown that this neuroprotective factor is produced in greater amounts with age, and it is absent under conditions of pathology, which leaves cells in the brain vulnerable to various forms of physiological stress. These findings, collected by several independent laboratories, have been linked to Parkinson’s disease (PD). In this study, we therefore aim to determine whether REST will prove an effective target for therapeutic intervention in PD.

Hypothesis: Using two different state-of-the-art PD preclinical models, we will assess whether re-introducing REST in neurons will alleviate Parkinsonian traits, particularly motor impairment. The findings will help us assess whether REST is a viable therapeutic target for PD.

Study Design: The preclinical models we propose to use display several Parkinsonian traits, such as movement impairments, neuronal loss or the pathologic accumulation of alpha-synuclein. Using advanced gait analysis, we will carefully study the changes in movement before and after the reintroduction of REST. We will also count the number of neurons before and after treatment and evaluate whether REST administration provides a neuroprotective function. Finally, we will analyze whether REST therapy reduces the pathological accumulation of alpha-synuclein, which should further protect the remaining neurons.

Impact on Diagnosis/Treatment of Parkinson’s disease: This study will determine whether REST is an appropriate target for PD. Because drug discovery is a very complicated and expensive process, establishing whether REST is a good target for PD is crucial before we invest time and effort in searching for compounds that will enhance its neuroprotective function.

Next Steps for Development: Should this study prove that REST is a viable target, we would attempt to find drugs that can activate this protein in the brain. A therapeutic REST activator could slow or halt neurodegeneration, which would provide significant relief for individuals with PD.


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