Motor neuron diseases, including ALS, sit at the intersection of RNA biology, proteostasis and metabolism. Our work in this area asks how nuclear architecture, architectural RNAs and chromatin remodeling govern the behavior of disease-linked RNA-binding proteins such as TDP-43 and FUS, and how their misregulation leads to motor neuron death.
Using Drosophila and neuronal systems, we have shown that chromatin remodelers (e.g. ISWI) and nuclear speckle RNAs (e.g. hsr-omega) actively organize the nuclear speckle environment that hosts TDP-43 and FUS. Disrupting this environment drives RBP mislocalization and disease-like post-translational modifications, placing nuclear speckles upstream of RBP pathology rather than as bystanders. On this mechanistic basis, we have built a suite of in vivo ALS models, including flies expressing the patient-derived TDP-43 G348C mutation, and we use them to dissect UBQLN2-dependent quality control, emerging roles of lipid metabolism and other modifiers of motor neuron survival. This program positions our group at the mechanistic core of how nuclear organization and proteostasis shape ALS and related disorders.
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