Project: Stress granules and proteostasis in motor neurons: towards a mechanistic understanding of ALS

Acronym CureALS (Reference Number: 50)
Duration 01/07/2016 - 30/06/2019
Project Topic Aging is associated with the development of neurodegenerative diseases. Young cells have mechanisms in place to prevent cellular decline, but with increasing age, the efficiency of cellular self-repair and metabolism decrease, inevitably leading to cellular demise. ALS and related motor neuron diseases are among the most severe age-related disorders, and therapeutic interventions are still unavailable. Due to the complex etiology of the disease, the mechanistic basis of ALS has been difficult to pinpoint. In recent years, evidence has been accumulating that ALS is caused or exacerbated by protein/RNA aggregates and a failure of the cellular stress response and the protein quality control (PQC) machinery. However, how these different processes are functionally connected and eventually lead to disease remains poorly understood. In this proposal, we will investigate the molecular underpinnings of motor neuron degeneration, focusing on the role of RNA/protein aggregates as key mediators of cellular decline. Our proposal is based on recent findings, which show that an impairment of the PQC machinery triggers a conversion of physiological RNP granules, so called stress granules, to an aberrant aggregated state. We hypothesize that the formation of these aberrant RNA/protein aggregates causes a derailment of prosurvival signaling, eventually triggering neuronal degeneration. As an experimental system, we will use motor neurons and glial cells derived from patient iPS cells, which will offer an unprecedented window into the disease. The goals of this proposal are to (i) study the molecular changes triggering the formation of RNA/protein aggregates in motor neurons and investigate how aggregation is affected by genetic, environmental and gender-related risk factors; (ii) study the role of the PQC machinery in the formation of RNA/protein aggregates, and investigate how genetic, environmental and gender-related factors affect PQC activity and neuronal health; (iii) identify drug-like compounds that prevent or reverse the formation of aberrant RNA/protein aggregates, restore a normal stress response and prevent neuronal degeneration. Our approach will offer definitive insight into the complex etiology of motor neuron disorders and will provide a solid mechanistic basis for diagnostics and therapy development.
Network JPco-fuND
Call Neurodegenerative diseases: risk and protective factors, longitudinal cohort approaches and advanced experimental models

Project partner

Number Name Role Country
1 Max Planck Society Coordinator Germany
2 Hebrew University of Jerusalem Partner Israel
3 Università degli Studi di Modena e Reggio Emilia Partner Italy
4 Universita' degli studi di Milano Partner Italy
5 Karolinska Institutet Partner Sweden
6 Technische Universität Dresden Partner Germany
7 University of Zurich Partner Switzerland