Functional implication of ubiquitinating and deubiquitinating mechanisms in TDP-43 proteinopathies

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which motor neurons in spinal cord and motor cortex are progressively lost. About 15% cases of ALS also develop the frontotemporal dementia (FTD), in which the frontotemporal lobar degeneration (FTLD) occurs in the frontal and temporal lobes of the brain. Among the pathologic commonalities in ALS and FTD is ubiquitin-positive cytoplasmic aggregation of TDP-43 that may reflect both its loss-of-function and gain-of-toxicity from proteostasis impairment. Deep understanding of how protein quality control mechanisms regulate TDP-43 proteinopathies still remains elusive. Recently, a growing body of evidence indicates that ubiquitinating and deubiquitinating pathways are critically engaged in the fate decision of aberrant or pathological TDP-43 proteins. E3 ubiquitin ligases coupled with deubiquitinating enzymes may influence the TDP-43-associated proteotoxicity through diverse events, such as protein stability, translocation, and stress granule or inclusion formation. In this article, we recapitulate our current understanding of how ubiquitinating and deubiquitinating mechanisms can modulate TDP-43 protein quality and its pathogenic nature, thus shedding light on developing targeted therapies for ALS and FTD by harnessing protein degradation machinery.

Involvement of heterologous ubiquitination including linear ubiquitination in Alzheimer’s disease and amyotrophic lateral sclerosis

“…Moreover, the age-dependent increase in the K63-ubiquitination of the CTFs of TDP-43 was identified ( Yin et al, 2021 ). The E2 of UBE2E3 (UbcH9), E3s such as parkin, VHL/Cul2, Znf179 (RNF112), Praja1, RNF220, and SCF cyclin F , and DUBs such as USP5, USP7, USP8, USP10, USP13, USP14, and CYLD, are reportedly involved in the ubiquitination and deubiquitination of TDP-43 ( Tran and Lee 2022 ), indicating that many E3s and DUBs regulate the spatiotemporal ubiquitin dynamics of TDP-43 in ALS.…”

Drosophila melanogaster as a model to study autophagy in neurodegenerative diseases induced by proteinopathies

“…It is characterized by a progressive neurodegeneration caused by an expansion of CAG at the 3′ end of the coding region of the ATXN3 gene, which from 12 to 40 repeat in the wild-type reaches more than 55 CAGs in the mutant form ( Klockgether et al, 2019 ). The gene encodes for a deubiquitinase (DUB), a class of enzymes that counteracts the action of ubiquitin and important for the control protein stability of TP-43 and HTT ( Doss-Pepe et al, 2003 ; van Well et al, 2019 ; Tran and Lee, 2022 ), responsible when mutated of ALS and HD, making DUBs potential targets for proteinopathies.…”

Unraveling the impact of disrupted nucleocytoplasmic transport systems in C9orf72-associated ALS

“…Over 90% of ALS cases and 45% of FTD cases exhibit TDP-43 pathology, with nuclear depletion and cytoplasmic aggregation of TDP-43 associated with both loss- and gain-of-function mechanisms, respectively. Several factors have been proposed to contribute to TDP-43 pathology, including posttranslational modifications such as ubiquitination (Buratti, 2018 ; Hans et al, 2020 ; Tran and Lee, 2022 ), phosphorylation (Gruijs da Silva et al, 2022 ; Pattle et al, 2023 ), acetylation (Cohen et al, 2015 ; Wang et al, 2017 ; Yu et al, 2021 ; Lu et al, 2022 ; Morato et al, 2022 ), as well as the generation of lower molecular weight isoforms (Xiao et al, 2015b ; Shenouda et al, 2018 , 2022 ; Hans et al, 2020 ; Weskamp et al, 2020 ; Keating et al, 2022 ; Tamaki and Urushitani, 2022 ). These modifications may influence TDP-43 stability, interactions with other proteins, its biophysical properties, and aggregation propensity (Cohen et al, 2015 ; Wang et al, 2017 ; Buratti, 2018 ; Shenouda et al, 2018 ; Gruijs da Silva et al, 2022 ; Keating et al, 2022 ; Liao et al, 2022 ; Sternburg et al, 2022 ; Tamaki and Urushitani, 2022 ).…”