Analysis of TDP-43 LLPS in Neurodegenerative Diseases
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Analysis of TDP-43 LLPS in Neurodegenerative Diseases

TAR DNA binding protein 43 kDA (TDP-43) is a highly conserved and ubiquitously expressed RNA/DNA binding protein belonging to the heterogeneous nuclear ribonucleoprotein (hnRNP) family. The dysfunction of TDP-43-related pathways is increasingly recognized as an important pathogenic mechanism in neurodegenerative diseases. In 2006, hyperphosphorylated and ubiquitinated TDP-43 cytoplasmic inclusions were identified as pathological features of amyotrophic lateral sclerosis (ALS) and frontotemporal lobe disease (FTLD). In these pathological deposits, TDP-43 undergoes numerous post-translational modifications (PTM), including polyubiquitination, hyperphosphorylation, and protein hydrolytic cleavage.

Fig. 1. Putative mechanisms by which TDP-43 exerts its pathogenic effects in TDP-43 proteinopathies.Fig. 1. Putative mechanisms by which TDP-43 exerts its pathogenic effects in TDP-43 proteinopathies. (Boer EMJ, et al., 2020)

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TDP-43 has been shown to undergo liquid-liquid phase separation (LLPS) in vitro and some of its functions are closely related to its ability to phase separate. TDP-43 mutations are associated with a growing number of neurodegenerative diseases. CD BioSciences offers specialized services to analyze LLPS of TDP-43 in neurodegenerative diseases.

We can analyze neurodegenerative diseases associated with TDP-43 and link these diseases to the structure and function of TDP-43 by detecting related genes.

Neurodegenerative Diseases Associated with TDP-43 Related Genes
Classical Amyotrophic Lateral Sclerosis ALS2, SETX, TARDBP, VAPB, ANG, UBQLN2, OPTN, PFN1, UNC13a, NEK1, C21orf2, SIGMAR1, DCTN1, MATR3, VCP, hnRNPA1/A2b1, NIPA1, TBK1, ATXN2, UBQLN2, SQSTM1
ALS-FTLD, ALS-ci/bi TARDBP, CHMP2b, TBK1, UBQLN2, SQSTM1, DCTN1, UNC13a
FTLD CHMP2b, GRN, SQSTM1, OPTN, TBK1, ATXN2
Perry Disease DCTN1
Facial Onset Sensory and Motor Neuronopathy (FOSMN) SOD1, SQSTM1, VCP, CHCHD10

Importantly, our team of experts is dedicated to developing therapeutic strategies for TDP-43 protein disease by removing TDP-43 protein aggregates and modulating other TDP-43 pathogenic processes. We offer cutting-edge in vivo, computer and cellular experiments to analyze the key molecular pathways of TDP-43-induced neurodegeneration, including:

  • Mutations in the TARDBP gene.
  • Dysregulation of RNA metabolism. We provide mouse model studies to support RNA metabolic dysregulation as a causative mechanism for TDP-43 proteinopathy.
  • Nuclear TDP-43 depletion.
  • Disordered nuclear transport.
  • Post-translational modifications of TDP-43 protein, including phosphorylation, ubiquitination, acetylation, poly ADP-ribosylation and cysteine oxidation.
  • Autophagy. We can analyze the role of TDP-43 as a regulator of autophagy to remove pathogenic TDP-43 oligomers.
  • Mitochondrial dysfunction. We can analyze the interaction between pathogenic TDP-43 and mitochondrial.

Furthermore, we systematically integrate these regulatory approaches with proteomic, transcriptomic, imaging, genetic, and epidemiological data to explore the pathogenesis of abnormal phase changes in TDP-43 and to develop potential therapeutic targets to prevent and treat these neurodegenerative diseases.

CD BioSciences aims to analyze the relationship between the genetic and molecular processes involved in TDP-43 dysfunction to help our clients develop therapeutic targets and novel biomarkers for the treatment of ALS and FTLD. If you are interested in our services, please feel free to contact us.

Reference

  1. Boer EMJ, et al. (2020) TDP-43 proteinopathies: a new wave of neurodegenerative diseases. J Neurol Neurosurg Psychiatry. 92(1):86-95.
For research use only, not intended for any clinical use.
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