Project: Common architecture of local proteome, transcriptome and translatome across Motor Neuron disorders

Acronym localMND (Reference Number: PATHWAYS-200-199)
Project Topic Motor neuron disorders (MNDs) are a group of neurodegenerative diseases affecting motor neurons, i.e. neurons that control skeletal muscle contraction to produce motion. Degeneration of motor neurons leads to progressive paralysis and severe disability. Although MNDs have a substantial effect on human health (1 in 300 people), no curative treatment exists. Despite their heterogeneity, MNDs share common pathogenic pathways, including abnormalities in RNA splicing and transport, ER stress and mitochondrial dysfunction. In the proposed study within the framework of the Multinational and Multidisciplinary projects for Pathway Analysis across Neurodegenerative Disease, we will combine the expertise of different labs - RNA biology (Chekulaeva), computational biology (Ulitsky), neurodegenerative disease research (Storkebaum) and clinical research (La Bella) - to perform network analyses across MNDs in order to elucidate the common mechanisms underlying neurodegeneration in MNDs. The neuron is a highly polarized cell, consisting of cell body and neurite extensions. Such polarity is crucial to neuronal function and relies largely on asymmetric subcellular translation and localization of RNAs and proteins. In our prior work, we have developed a neurite/soma fractionation scheme in combination with mass spectrometry, RNA-seq and ribosome profiling analyses, to identify proteins and RNAs that are differentially localized and translated between neurites and soma of neuronal cells. Here we will apply this profiling scheme to motor neurons and their MNDs models, generated through in vitro differentiation procedures from stem cells (Chekulaeva). This study will yield a thorough picture of local proteome, transcriptome and translatome of motor neurons and changes caused by mutations found in MNDs, which is an important and poorly investigated theme in neurodegenerative research. Moreover, this combination of approaches will allow us for the first time to confidently identify and compare activities of both protein-coding genes and long non-coding RNAs (lncRNAs) across these conditions. We will perform integrative computational data analysis to identify common players (mRNAs, proteins, lncRNAs) that change their expression and/or localization pattern in multiple MND models (Ulitsky). We will follow with validation studies and dissection of the underlying mechanisms in induced motor neurons (Chekulaeva) and in vivo models (Storkebaum). This combined analysis will shed new light on the fundamental links between different MNDs and suggest new approaches for their treatment.
Network JPco-fuND

Project partner

Number Name Role Country
1 Max Delbrück Center for Molecular Medicine in the Helmholtz Association Coordinator Germany
2 Weizmann Institute of Science Partner Israel
3 Radboud University Partner Netherlands
4 ALS Clinical Research Center Partner Italy