Which TDP-43 aggregates are toxic in ALS?

Valle, Cristiana; Carrı̀, Maria Teresa

doi:10.18632/oncotarget.13461

Cited by 2 publications

(1 citation statement)

References 8 publications

(9 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cleavage products of TDP-43 are degraded by the proteasome and through autophagy[23–25]. However, whether aggregated and cleaved TDP-43 actually mediate disease or are non-toxic bi-products of physiological TDP-43 processing[26, 27] is unclear.…”

Section: Introductionmentioning

confidence: 99%

Inhibiting glycogen synthase kinase 3 suppresses TDP-43-mediated neurotoxicity in a caspase-dependant manner

White

Massenzio

et al. 2021

Preprint

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) is a progressive and ultimately fatal disease spectrum characterised by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Current disease modifying drugs have modest effects and novel therapies are sorely needed. We previously showed that deletion of glycogen synthase kinase-3 (GSK3) suppresses TDP-43-mediated motor neuron degeneration in Drosophila. Here, we investigated the potential of GSK3 inhibition to ameliorate TDP43-mediated toxicity in mammalian neurons. Expression of TDP-43 was found to both activate GSK3 and promote caspase mediated cleavage of TDP-43. Inhibition of GSK3 reduced the abundance of full-length and cleaved TDP-43 in rodent neurons expressing wild-type or disease-associated mutant TDP-43 and also ameliorated neurotoxicity. Our results suggest that TDP-43 turnover is promoted by GSK3 inhibition in a caspase-dependent manner, and that targeting GSK3 activity could have therapeutic value.

show abstract

Section: Introductionmentioning

confidence: 99%

Inhibiting glycogen synthase kinase 3 suppresses TDP-43-mediated neurotoxicity in a caspase-dependant manner

White

Massenzio

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

The N-terminal dimerization is required for TDP-43 splicing activity

Jiang

Xue

Hong

et al. 2017

Sci Rep

110

View full text Add to dashboard Cite

TDP-43 is a nuclear factor that functions in promoting pre-mRNA splicing. Deletion of the N-terminal domain (NTD) and nuclear localization signal (NLS) (i.e., TDP-35) results in mislocalization to cytoplasm and formation of inclusions. However, how the NTD functions in TDP-43 activity and proteinopathy remains largely unknown. Here, we studied the structure and function of the NTD in inclusion formation and pre-mRNA splicing of TDP-43 by using biochemical and biophysical approaches. We found that TDP-43 NTD forms a homodimer in solution in a concentration-dependent manner, and formation of intermolecular disulfide results in further tetramerization. Based on the NMR structure of TDP-43 NTD, the dimerization interface centered on Leu71 and Val72 around the β7-strand was defined by mutagenesis and size-exclusion chromatography. Cell experiments revealed that the N-terminal dimerization plays roles in protecting TDP-43 against formation of cytoplasmic inclusions and enhancing pre-mRNA splicing activity of TDP-43 in nucleus. This study may provide mechanistic insights into the physiological function of TDP-43 and its related proteinopathies.

show abstract

Which TDP-43 aggregates are toxic in ALS?

Cited by 2 publications

References 8 publications

Inhibiting glycogen synthase kinase 3 suppresses TDP-43-mediated neurotoxicity in a caspase-dependant manner

Inhibiting glycogen synthase kinase 3 suppresses TDP-43-mediated neurotoxicity in a caspase-dependant manner

The N-terminal dimerization is required for TDP-43 splicing activity

Contact Info

Product

Resources

About