RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

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RNA decay is a critical component of RNA homeostasis. Transcriptionally active cells such as neurons have developed intricate pathways for regulating RNA turnover and balancing this process with RNA synthesis. During the initial funding period, we uncovered widespread abnormalities in RNA stability in cells from individuals with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), implicating dysfunctional RNA clearance pathways in disease pathogenesis. We also showed that many of these abnormalities could be recapitulated by the deposition of TDP43, a nuclear RNA binding protein and splicing factor that is mislocalized to the cytoplasm in >95% of ALS patients and the most common subtype of FTLD (FTLD-TDP). In probing the downstream consequences of TDP43 deposition, we discovered that TDP43 accumulation preferentially affects the splicing of mRNAs encoding ribosomal proteins, leading to excessive intron retention and mRNA destabilization. Based on these results, we hypothesize that TDP43 mislocalization and accumulation in ALS and FTLD-TDP destabilizes ribosomal protein-encoding mRNAs, compromising translation and interfering with RNA decay mechanisms that rely on active translation, including nonsense-mediated RNA decay (NMD). Together, these phenomena would be expected to trigger a vicious cycle culminating in RNA and protein dyshomeostasis, and eventually neurodegeneration. The current proposal builds on data from the initial funding period to (i) elucidate the mechanism of RNA destabilization by TDP43, (ii) categorize the impact of RNA destabilization on protein translation and RNA homeostasis; and (iii) evaluate the therapeutic potential of two promising genetic modifiers, UPF1 and YTHDF2, for their ability to restore RNA homeostasis and extend neuronal survival in human neuron models of ALS and FTLD-TDP. These goals are mirrored by our long-term objectives: to crystalize the function of TDP43 in neurons and other cell types, and harness this information to devise effective neuroprotective strategies for ALS, FTLD-TDP and related TDP43-proteinopathies.