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