Long noncoding RNAs in TDP-43 and FUS/TLS-related frontotemporal lobar degeneration (FTLD)

Frontotemporal lobar degeneration (FTLD) defines a spectrum of heterogeneous neurodegenerative disorders characterized by the progressive deterioration of the frontal and anterior temporal lobes of the brain. FTLD is histopathologically classified according to the presence of neuropathological protein aggregates. Two of the major pathologies, FTLD-TDP and FTLD-FUS, are characterized by the abnormal accumulation in cytoplasmic inclusions of RNA-binding proteins (RBPs) - TDP-43 and FUS/TLS, respectively. That suggests that a crucial common downstream pathway leading to cell death might involve the disruption of RNA-based mechanisms. Long noncoding RNAs have emerged as key regulators in the different layers of gene regulation. Increasing evidence suggests that long non-coding RNAs (lncRNAs) may have pivotal biological functions in the brain and, not surprisingly, they have been implicated with neurodegenerative diseases, like Alzheimer's and Parkinson's diseases. Recent studies report that FTLD/ALS-related proteins TDP-43 and FUS/TLS bind lncRNAs, and that several lncRNAs have binding sites for TDP-43 and/or FUS/TLS. These findings raise important questions about how TDP-43 and FUS/TLS pathologies can affect lncRNA-based mechanisms. One alternative is that TDP-43 and FUS/TLS regulate lncRNA transcription or transcript stability. In fact, it has been demonstrated that lncRNAs are dysregulated upon either depletion or unavailability of functional TDP-43 or FUS/TLS in a range of different models and diseases, including post-mortem samples from subjects with FTLD-TDP. The second alternative is that the binding to TDP-43 or FUS/TLS would enable lncRNAs to perform their cellular function. In this case, the unavailability of these RBPs would disrupt functional properties of lncRNAs, without necessarily altering their cellular levels. It has been experimentally demonstrated that the cellular function of some lncRNAs is strictly dependent on the direct binding to TDP-43 or FUS/TLS.