Modulating Aging-controlling Pathways in Pre-clinical models of Parkinsonís Disease
Target Validation, 2015
Objective/Rationale: † † † † † ††
Because of its unknown etiology and its link to aging, Parkinsonís disease is often seen as a stochastic and pathological acceleration of aging. Using a high-content screening we recently identified an evolutionary conserved pathway that is a key regulator of aging. Further investigation revealed that this pathway is able to protect nigral dopamine neurons in various cellular and in vivo models of Parkinson.
We will combine different genetic approaches to modulate this aging-governing pathway and determine whether this can not only prevent neurodegeneration but also reverse motor and non-motor symptoms in complementary models of Parkinsonís disease. We will also test whether partial inhibition of this signaling pathway is sufficient to provide a therapeutic effect. The impact of these manipulations will be examined using behavioral, histological, molecular and biochemical analysis.
Relevance to Diagnosis/Treatment of Parkinsonís Disease: † † † † † † † † † ††
We propose that the manipulation of pathways governing cellular aging may lead to the identification of interesting therapeutic targets. These pathways can also provide readily detectable biomarkers and a causative links between Parkinsonís disease and its primary risk factor. This project will also help bridge the gap between healthy and pathological aging.
Anticipated Outcome: † † † † †
The possibility of linking a signaling pathway or biological substrates that can be manipulated pharmacologically to the sporadic form of Parkinsonís disease opens exciting avenues of research for therapeutic approaches. If successful, this project will provide a proof-of-concept that the development of specific inhibitors of this pathway may hold great promise for the treatment of Parkinsonís disease.
We recently identified a pathway -- a series of chemical reactions inside the cell -- that governs the process of aging. We also showed that this pathway is able to protect dopamine-producing nerve cells in models of Parkinson's disease (PD). In this study, we aimed to determine whether manipulating this pathway prevents neurodegeneration and reverses motor and non-motor symptoms of PD.
We tested the effect of pathway manipulation in two pre-clinical models with Parkinson's features. In the first model, the pathway was blocked in a large brain region, partially preventing the development of motor and non-motor symptoms. Consistently, communication between the nerve cells improved, inflammation diminished and accumulation of alpha-synuclein clumps -- the pathological hallmark of PD -- in the brain reduced.
In the second model, we demonstrated that slowing this aging pathway when disease symptoms are already present restores the motor function. This finding correlated with the improvement of histological, biochemical and molecular indicators of disease. These positive results confirmed our hypothesis that modulation of pathways governing aging -- the greatest risk factor for Parkinson's disease -- represents a potential therapeutic strategy and warrants further clinical development.
Presentations & Publications
The results obtained have not been reported yet to the community. They will be part of a publication currently in preparation.
Assistant Investigator at Telethon Institute of Genetics and Medicine (TIGEM) Ė Telethon Foundation
Location: Pozzuoli, Italy