Neurodegenerative diseases have a multitude of factors contributing to their pathogenesis. In the first of our Weekly Gene features covering pathogenic genes of neurodegenerative diseases, we review the functionality of TARDBP. This review, as well as the upcoming Weekly Gene articles, aim to help researchers explore potential therapeutics for neurogenerative diseases.
Background Information – TARDBP Gene
|
Species |
Human |
Mouse |
Rat |
|
Chromosome |
1 |
4 |
5 |
|
Full Length (bp) |
17,875 |
14,834 |
10,144 |
|
mRNA (nt) |
4,185 |
7,454 |
2,923 |
|
Numbers of exons |
7 |
8 |
8 |
|
Numbers of amino acids |
414 |
414 |
414 |
|
Gene Family |
PABPC4, PABPC1, PABPC1L, PABPC3, RBM45 |
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Overview of TARDBP Gene Research
The TARDBP gene encodes TAR DNA binding protein 43 (TDP-43) - which can bind to either DNA and RNA, and plays an important role in intracellular RNA transcription, splicing and regulation of mRNA stability. It is known that the protein inclusion bodies formed by the aggregation and ubiquitination of the protein have been detected in the damaged area cells of patients with either amyotrophic late sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Additionally, abnormal changes in TDP-43 can be detected in about ~1/3 of Alzheimer disease (AD) patients. At present, over 40 TARDBP mutations have been identified from familial ALS cases.
Figure 1: TDP-43 structure and disease-related mutations. From left to right, the N-terminal domain (NTD) of TARDBP contains 101 amino acids; two RNA recognition motifs (RRM), namely RRM1 with 91 amino acids and RRM2 with 74 amino acids; NTD also has a 16-amino acid nuclear localization signal (NLS); an 11-amino acid nuclear export signal (NES); finally the glycine-rich C-terminus, with mitochondrial localization regions (M1, M3 and M2) dispersed in different areas. In addition, the glycine-rich region also contains a small section of glutamic acid/aspartic acid enriched area (Q/N) in the glycine enriched area. The whole glycine-rich region witnesses the most frequent ALS-associated mutations. The mutation shown in different colors to represent separate diseases. For example, sALS refers to sporadic ALS-associated mutation, fALS familial ALS- associated mutation, and FTLD frontotemporal dementia. The protein map below represents 3D structure of N-terminal, two RNA recognition regions, and the C-terminus of TDP-43, respectively. Source: https://doi.org/10.3389/fnmol.2019.00025
Figure 2: Functions of TDP-43. TDP-43 is involved in mRNA-related processes in cell nucleus, such as transcription, splicing, maintaining RNA stability, and processing of miRNA and lncRNA. Its main functions are completed in the nucleus, yet it also shuttles between nucleus and cytoplasm. In the cytoplasm, TDP-43 is involved in the formation of stress granules and ribonucleoprotein (RNP) transport granules, as well as the translation and other processes related to the latter.
https://doi.org/10.3389/fnmol.2019.00025.
Proteins Related to TDP-43
|
Classifications |
Proteins |
Descriptions |
|---|---|---|
|
RNA-binding protein |
FUS |
TDP-43 interacts with some amino acids of FUS. The ALS-associated mutation of TDP-43 can enhance its interaction with FUS. Interfering with or disrupting such interaction can reduce the expression of histone deacetylase 6 (HDAC6) mRNA. |
|
hnRNPAl and hnRNPA2/Bl |
hnRNPs interact with the C-terminal area of TDP-43 to regulate mRNA splicing and the feedback auto-regulation of TDP-43. |
|
|
TIA1 |
TIA1 acts to form stress granule (SG) and helps to bind SGs and RNA-dependent SGs to TDP-43. TIA1 mutation identified in ALS increases its tendency to dissociate with TDP-43, changes the percentage of normal disintegration of SGs and promotes accumulation of TDP-43 within SGs.
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RBM45 |
RBM45 accumulates in the inclusion bodies of ALS and FTLD patients. The aggregates of RBM45 and TDP-43 are co-localized in the cytoplasm. There are no reports of RBM45 mutations in ALS. However, the existing RBM45 mutations can cause cytoplasmic aggregates of TDP-43 and impair mitochondrial function.
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Ataxin-2 |
The repetitive increment of polyglutamine in Ataxin-2 is a genetic risk factor for ALS. Ataxin-2 containing 22 glutamines (Gln/Q) is normal, while 27-33 Q may cause increased ALS risk. If the value is >34 Q, it is related to spinocerebellar ataxia type 2 (SCA2). The interaction between Ataxin-2 and TDP-43 depends on RNA. The repetitive increment of polyglutamine in ataxin-2 is also found in ALS, but in these cases it increases cleavage and phosphorylation of TDP-43.
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Matrin3 |
According to co-immunoprecipitation experiments, the interaction between Matrin3 and TDP-43 is dependent on the presence of RNA. The S85C mutation of Matrin3 can enhance its interaction with TDP-43. |
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|
Immunoreactions |
p62 and p65 (NFkB) |
TDP-43 interacts with NFkB and acts as a co-activator of NFkB in the glial cells and nerve cells of ALS patients, thus inducing the generation of proinflammatory cytokines and neurotoxic mediators. |
|
Heat shock response and proteolysis |
Hsp40 and Hsp70 |
The Hsp40/Hsp70 co-chaperone/chaperone system interacts with the c-terminal region of TDP-43 to inhibit heat shock-induced aggregation of TDP-43. The heat shock protein DNAJB2is related to Hsp70 and regulates its clearance by maintaining the soluble state of TDP-43. The overexpression of Sis1, the homologous gene of Hsp40 in yeast, reduces the toxicity TDP-43 in the yeast model. |
|
DNAJB1 and DNAJB6 PDI |
The overexpression of DNAJB1 (Hsp40 protein, mammalian Sis1 homolog) reduces TDP-43-mediated toxicity of rodent primary cortical neurons. The overexpression of DNAJB6 can inhibit the formation of heat shock-induced nuclear aggregation of TDP-43. DNAJB6 interacts with the disordered c-terminal domain of TDP-43, regulates the aggregation of TDP-43, and affects its interaction with other RNA-binding partners. |
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|
PDI |
The molecular chaperone PDI interacts with mutant TDP-43, both of which are co-localized in spinal cord neuron cells. PDI may also be involved in preventing abnormal cysteine cross-linking in TDP-43. |
|
|
Parkin |
E3-ubiquitin ligase Parkin ubiquitinates TDP-43, forming a multi-protein complex and inducing TDP-43 into cytoplasmic inclusions. |
|
|
Ubiquilinl and Ubiquilin2 |
Mutated ubiquitin proteins are involved in the aberrations of proteasomes and autophagy pathways. Ubiquilin2 binds to TDP-43 with high affinity and induces accumulation of polyubiquitin inclusions within neuronal cells. |
|
|
Optineurin |
Optineurin mutations may cause blindness and glaucoma. Recently, optineurin has been associated with ALS and TDP-43 in sporadic inclusion body myositis (sIBM). |
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Oxidative stress |
SOD1 |
The ALS-associated SOD1 mutant interacts with TDP-43 to form a detergent-insoluble component. Mutant SOD1 and TDP-43 act synergistically to regulate the stability of neurofilament mRNA. |
|
CHCHD10 |
CHCHD10 is a mitochondrial protein that exists at the junction of the intermembrane gap and functions to regulate mitochondrial structure and oxidative phosphorylation. TDP-43 can interact with CHCHD10 and induce its localization in the nucleus, while mutations in CHCHD10 can cause the aggregation of TDP-43 in the cytoplasm.
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Conclusions
Among neurodegenerative diseases, the quantity of familial genes related to ALS accounts for the largest proportion, which explains the huge quantity of ALS model types. However, this also accounts for the small mutation frequency of each gene seen for familial cases, as each mutation is rarely seen. Cyagen has already developed the corresponding disease models for the most common ALS-associated gene mutations – including SOD1 and TDP-43. We are also developing models for other ALS-associated genes.
>> Search Your Gene of Interest
|
Genes |
Full name |
NCBIID |
Status |
|---|---|---|---|
|
Actin Beta |
11461 |
Cryopreserved sperm |
|
|
Activating Transcription Factor 4 |
11911 |
Cryopreserved sperm |
|
|
BCL2 Associated X, Apoptosis Regulator |
12028 |
Cryopreserved sperm |
|
|
BCL2 Apoptosis Regulator |
12043 |
Cryopreserved sperm |
|
|
Caspase 3 |
12367 |
Cryopreserved sperm |
|
|
Catalase |
12359 |
Cryopreserved sperm |
|
|
Mitogen-Activated Protein Kinase 14 |
26416 |
Cryopreserved sperm |
|
|
Mechanistic Target Of Rapamycin Kinase |
56717 |
Cryopreserved sperm |
|
|
Nitric Oxide Synthase 2 |
18126 |
Cryopreserved sperm |
|
|
Neuregulin 1 |
211323 |
Cryopreserved sperm |
|
|
Parkin RBR E3 Ubiquitin Protein Ligase |
50873 |
Cryopreserved sperm |
|
|
Rac Family Small GTPase 1 |
19353 |
Cryopreserved sperm |
|
|
Superoxide Dismutase 1 |
20655 |
Cryopreserved sperm |
|
|
Sequestosome 1 |
18412 |
Cryopreserved sperm |
|
|
Tumor Necrosis Factor |
21926 |
Cryopreserved sperm |
|
|
TNF Receptor Superfamily Member 1A |
21937 |
Cryopreserved sperm |
|
|
TNF Receptor Superfamily Member IB |
21938 |
Cryopreserved sperm |
|
|
Tumor Protein P53 |
22059 |
Cryopreserved sperm |
|
|
Tubulin Beta 3 Class III |
22152 |
Cryopreserved sperm |
|
|
X-Box Binding Protein 1 |
22433 |
Cryopreserved sperm |
Neurodegenerative Disease Related Resource:
>> Advancing Neurodegenerative Disease Research with Animal Models
>> SNCA: A Pathogenic Gene of Neurodegenerative Diseases
References:
1. Prasad A, Bharathi V, Sivalingam V, Girdhar A, Patel BK. Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis. Front Mol Neurosci. 2019 Feb 14;12:25. doi: 10.3389/fnmol.2019.00025. PMID: 30837838; PMCID: PMC6382748.
2. Kukreja L, Shahidehpour R, Kim G, Keegan J, Sadleir KR, Russell T, Csernansky J, Mesulam M, Vassar RJ, Wang L, Dong H, Geula C. Differential Neurotoxicity Related to Tetracycline Transactivator and TDP-43 Expression in Conditional TDP-43 Mouse Model of Frontotemporal Lobar Degeneration. J Neurosci. 2018 Jul 4;38(27):6045-6062. doi: 10.1523/JNEUROSCI.1836-17.2018. Epub 2018 May 28. PMID: 29807909; PMCID: PMC6031584.
