Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation
Top Cited Papers
- 2 March 2021
- journal article
- review article
- Published by Springer Science and Business Media LLC in Nature Reviews Neuroscience
- Vol. 22 (4), 197-208
- https://doi.org/10.1038/s41583-021-00431-1
Abstract
Cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP43; also known as TARDBP or TDP-43) is a key pathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP43 typically resides in the nucleus but can shuttle between the nucleus and the cytoplasm to exert its multiple functions, which include regulation of the splicing, trafficking and stabilization of RNA. Cytoplasmic mislocalization and nuclear loss of TDP43 have both been associated with ALS and FTD, suggesting that calibrated levels and correct localization of TDP43 — achieved through an autoregulatory loop and tightly controlled nucleocytoplasmic transport — safeguard its normal function. Furthermore, TDP43 can undergo phase transitions, including its dispersion into liquid droplets and its accumulation into irreversible cytoplasmic aggregates. Thus, autoregulation, nucleocytoplasmic transport and phase transition are all part of an intrinsic control system regulating the physiological levels and localization of TDP43, and together are essential for the cellular homeostasis that is affected in neurodegenerative disease.Keywords
This publication has 142 references indexed in Scilit:
- Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALSNeuron, 2011
- A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTDNeuron, 2011
- Characterizing the RNA targets and position-dependent splicing regulation by TDP-43Nature Neuroscience, 2011
- TDP-43 regulates its mRNA levels through a negative feedback loopThe EMBO Journal, 2010
- Global Analysis of TDP-43 Interacting Proteins Reveals Strong Association with RNA Splicing and Translation MachineryJournal of Proteome Research, 2009
- TARDBP 3′-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathyActa Neuropathologica, 2009
- Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathiesActa Neuropathologica, 2009
- Phosphorylated TDP‐43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosisAnnals of Neurology, 2008
- Atomic structures of amyloid cross-β spines reveal varied steric zippersNature, 2007
- TDP‐43 immunoreactivity in hippocampal sclerosis and Alzheimer's diseaseAnnals of Neurology, 2007