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Project Topic
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Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Parkinson’s disease (PD) are distinct neurodegenerative disorders, but share a common set of stress signalling pathways and susceptibility genes. Recent genetic and molecular studies highlighted deregulation of RNA processing, formation of stress granules, and stress-induced modifications of RNAs as key processes in these disorders. Of particular recent interest are a new class of small non-coding RNA (sncRNA) derived from tRNA fragments (‘tiRNA’). These are generated in response to neuronal stress, inhibit protein translation, regulate gene expression, and modify neuron and stem cell survival. RNA-NEURO partners identified proteins that generate tiRNAs as susceptibility and stress-response genes in ALS and PD, and developed state-of-the-art analysis pipelines for sncRNA sequencing and modification analyses suitable for preclinical and clinical systems studies. The aim of RNA-NEURO is to systematically analyze the disease-specific ‘fingerprint’ of tiRNA and other sncRNA in ALS, FTD and PD in preclinical models and clinical samples, explore their relation to stress signaling during disease progression, and determine their effect on neuronal survival and stem cell fate. RNA-NEURO realizes that the complexity of tiRNA and sncRNA biology can only be tackled through advanced bioinformatics, systems biology and data integration strategies, and will perform detailed systems studies that will allow for the analysis of genome-wide stress response regulation by tiRNAs and sncRNAs. RNA-NEURO will deliver a systematic evaluation of these new signaling molecules, explore their role as therapeutic targets, and aims to deliver easily accessible and detectable, diagnostic and prognostic biomarkers for ALS, FTD, and PD. 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.
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