Protein-RNA complexes & ALS: insights from iCLIP

Mutations in several RNA binding proteins (RBPs) cause ALS, including TDP43, hnRNPA1, hnRNPA2/B1, FUS and MATRIN3. Disease-causing mutations are most often concentrated within the intrinsically disordered regions (IDRs) of these RBPs. To understand the mechanisms of these mutations, we and others study how these RBPs assemble into larger protein-RNA complexes. One approach we take towards this purpose is to study their protein-RNA interactions with the use of individualnucleotide resolution UV crosslinking and immunoprecipitation (iCLIP), RNA-RNA interactions with Mass Spectrometry, and their function with RNA-Seq and PolyASeq. Our study indicates that the IDRs serve as a docking platform for protein-protein interactions, which in turn affect the RNA binding properties of RBPs. Since ALS and all neurodegenerative diseases are linked to aging, we also wish to understand how their causative mechanisms are linked to the interplay of molecular events and cellular changes that take place upon aging in different brain regions. For this purpose, we characterized aging-altered gene expression changes across 10 human brain regions from 480 individuals ranging in age from 16 to 106. We found that astrocyte and oligodendrocyte-specific, but not neuron-specific genes shift their regional expression patterns upon aging, particularly in the hippocampus and substantia nigra, while the expression of microglia and endothelial-specific genes increase in all brain regions. In line with these changes, high-resolution immunohistochemistry demonstrated decreased numbers of oligodendrocytes and of neuronal subpopulations in the aging brain cortex, and glial-specific genes predict age with greater precision than neuron-specific genes. I will discuss the role that proteinRNA complexes may play in regulating cellular fates, and in neuron-glia interactions in aging and late-life diseases.