Seminars

Common genetic loci and pathological signatures identified in the past decade have unified two seemingly different adult-onset neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which affect predominantly the motor and cognitive system, respectively. In particular, mutations in two nucleic-acid binding proteins, TDP-43 and FUS/TLS, are causal for both diseases, and the pathological TDP-43 and FUS inclusions accounts for the majority of ALS and ~55% of FTD patients. Such gene-pathology connection is commonly seen in neurodegenerative diseases, which suggests that distinct initiating events might be funneled into a pathogenic pathway leading to the same endpoint for the disease.
To address the molecular and cellular mechanisms by which dysfunctions in FUS/TLS cause damages on motor and cognitive functions, we combined mouse models with genomic methodologies to elucidate the normal and pathophysiological functions of FUS/TLS. Molecularly, FUS is known to participate in biogenesis of cellular RNAs, including mRNAs and microRNAs (miRNAs). Each miRNA species can modulate multiple mRNAs that function in a certain biological pathway, and changes of cellular states are often associated with characteristic changes of miRNA expression profiles. Our current study has identified miRNA-RNA relationship that may be underlying the selective neuron death in ALS and FTD.