Molecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD
Abstract
:1. Introduction
2. Pathogenic Mechanisms of TDP-43 in Cell and Animal Models
2.1. Neuron Morphology and Axonal Degeneration
2.2. Post-Translational Modifications
2.2.1. Cleavage
C-Terminal Fragments
2.2.2. Acetylation
2.2.3. Ubiquitination
2.2.4. SUMOylation
2.2.5. Phosphorylation and Aggregation
Mutant TDP-43 Proteins
Oligomerization
Aggregate Toxicity
2.3. Loss of Nuclear Function
2.3.1. RNA Splicing and RNA Instability
Autoregulation
mRNP Granules
Splicing
RNA Binding and Regulation of Gene Expression
2.4. Gain of Toxic Cytoplasmic Function
2.4.1. Stress Granules
2.4.2. Phase Separation
2.4.3. Impaired Axonal Transport
2.4.4. Mitochondrial Dysfunction
TDP-43 and Mitochondrial mRNA Regulation
Mitochondrial Structural and Functional Abnormalities
Oxidative Stress
2.4.5. Proteostasis
ER Stress and the Unfolded Protein Response
Ubiquitin-Proteasome System
Autophagy
2.5. Non-Cell-Autonomous Mechanisms
2.5.1. Gliosis
2.5.2. Prion-Like Propagation
2.6. Other
AMPK Signaling
3. Discussion
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
aa | amino acid |
ALS | amyotrophic lateral sclerosis |
AMP | adenosine 3′, 5′-monophosphate |
AMPA | α-amino-3-hydroxy-5-methyl-4-isoxazolepropinionic acid |
AMPK | AMP-activated protein kinase |
Ca2+ | calcium |
CK1 | casein kinase 1ε |
CTF | C-terminal fragment |
eIF2α | eukaryotic initiation factor 2 alpha |
EEAT2 | excitatory amino acid transporter 2 |
ENU | N -ethyl-N-nitrosurea |
ER | endoplasmic reticulum |
FTD-TDP | frontotemporal degeneration associated with TDP-43 pathology |
FTLD | frontotemporal lobar degeneration |
G3BP | RasGAP-association endoribonuclease |
G4-RNA | G-quadruplex-RNA |
GSK-3β | glycogen synthase kinase 3β |
LLPS | liquid–liquid phase separation |
MALAT | metastasis-associated lung adenocarcinoma transcript 1 (also known as NEAT2; nuclear paraspeckle assembly transcript 2) |
miRNA | micro RNA |
mRNA | messenger ribonucleic acid |
mTOR | mammalian target of rapamycin |
NEAT1 | nuclear paraspeckle assembly transcript 1 |
NES | nuclear export signal |
NeuN | neuronal nuclei |
neuroLNC | neuron-specific long-non-coding RNA |
NLS | nuclear localization signal |
NMJ | neuromuscular junction |
PARP-1 | poly-(ADP-ribose) polymerase-1 |
PINK1 | PTEN-induced putative kinase 1 |
PP2A | protein phosphatase 2A |
PSF | proline-glutamine rich |
PTM | post-translational modification |
RBP | RNA-binding protein |
RNA | ribonucleic acid |
RNS | reactive nitrogen species |
ROS | reactive oxygen species |
RRM | RNA recognition motif |
SURF | SMG1, UPF1 and eRF1 and 2 |
TARDBP | TAR-DNA-binding protein 43 |
TBK1 | tank-binding kinase 1 |
TDP-43 | TAR-DNA-binding protein 43 |
TFEB | transcription factor EB |
TIA-1 | T-cell intracellular antigen 1 |
UPR | unfolded protein response |
UPS | ubiquitin proteasome system |
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Decreased Nuclear Localization | CTF Formed | Phosphorylation | Co-Aggregation with Wild Type | Increased Aggregation/Insolubility | Increased Half-Life | |
---|---|---|---|---|---|---|
p.D169G | Y [73] | Y [71] | Y [42] | |||
p.K181E | Y [71] | |||||
p.K263E | Y [71] | |||||
p.G287S | N [42] | |||||
p.G290A | N [28] | Y [28] | Y [28] | Y [28] N [42] | ||
p.S292N | Y [28] | Y [28] | Y [28] | Y [28] | ||
p.G294A | Y [42] | |||||
p.G294V | N [28] | Y [28] | Y [28] | Y [28] | ||
p.G298S | N [28] | Y [28] | Y [28] | Y [28] N [42] | Y [28] | |
p.A315T | Y [28] | Y [28,50,74] | Y [28] | Y [28,48,51,74,75] N [42,74] | Y [28] | |
p.A315E | N [28] | Y [28] | Y [28] | Y [28] | ||
p.M331V | Y [28] | Y [28] | Y [28] | Y [28] | ||
p.S332N | N [28] | Y [28] | Y [28] | Y [28] | ||
p.M337V | Y [25] N [28] | Y [28] | Y [28] | Y [28,42,75] N [29,47] | Y [28] | |
p.Q331K | Y [25,55] | Y [55] | Y [42] | |||
p.Q343R | Y [28] | Y [28] | Y [28] | Y [28,75] | Y [28] | |
p.N345K | Y [28] | Y [28] | Y [28] | Y [28] | ||
p.G348C | N [28] | Y [28] | Y [28] | Y [28] N [42] | Y [28] | |
p.G348V | N [28] | Y [28] | Y [28] | Y [28] | ||
p.N352S | Y [28] | Y [28] | Y [28] | Y [28] | Y [28] | |
p.R361S | N [42] | |||||
p.Y374X | Y [47] | |||||
p.N378D | Y [28] | Y [28] | Y [28] | Y [28] | ||
p.S379P | Y [28] | Y [28] | Y [28] | Y [28] | ||
p.A382T | Y [28] | Y [28] | Y [28] | Y [28] N [29,42,48] | Y [28] | |
p.I383V | Y [28] | Y [28] | Y [28] | Y [28] | ||
p.N390D | Y [42] | |||||
p.N390S | Y [42] | |||||
p.S393L | Y [28] | Y [28] | Y [28] | Y [28] | ||
162-414 | Y [45] | |||||
167-414 | N [47] | |||||
173-414 | N [47] | |||||
178-414 | N [47] | |||||
183-414 | N [47] | |||||
188-414 | Y [47] | single nuclear inclusion. Y [47] | ||||
193-414 | Y [47] | single nuclear inclusion. Y [47] | ||||
198-414 | Y [47] | single nuclear inclusion. Y [47] | ||||
203-414 | Y [47] | single nuclear inclusion. Y [47] | ||||
208-414 | Y [45] | Y [47,48,50] | multiple cytoplasmic inclusions. Y [47,48,50] | |||
213-414 | Y [47] | multiple cytoplasmic inclusions. Y [47] | ||||
220-414 | Y [47] | multiple cytoplasmic inclusions. Y [47] | ||||
225-414 | Y [47] | multiple cytoplasmic inclusions. Y [47] |
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Wood, A.; Gurfinkel, Y.; Polain, N.; Lamont, W.; Lyn Rea, S. Molecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD. Int. J. Mol. Sci. 2021, 22, 4705. https://doi.org/10.3390/ijms22094705
Wood A, Gurfinkel Y, Polain N, Lamont W, Lyn Rea S. Molecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD. International Journal of Molecular Sciences. 2021; 22(9):4705. https://doi.org/10.3390/ijms22094705
Chicago/Turabian StyleWood, Alistair, Yuval Gurfinkel, Nicole Polain, Wesley Lamont, and Sarah Lyn Rea. 2021. "Molecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD" International Journal of Molecular Sciences 22, no. 9: 4705. https://doi.org/10.3390/ijms22094705