Abstract
Nuclear depletion, abnormal modification, and cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) are linked to a group of fatal neurodegenerative diseases called TDP-43 proteinopathies, which include amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Although our understanding of the physiological function of TDP-43 is rapidly advancing, the molecular mechanisms associated with its pathogenesis remain poorly understood. Accumulating evidence suggests that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are important players in TDP-43 pathology. However, while neurons derived from autopsied ALS and FTLD patients revealed TDP-43 deposits in the ER and displayed UPR activation, data originated from in vitro and in vivo TDP-43 models produced contradictory results. In this review, we will explore the complex interplay between TDP-43 pathology, ER stress, and the UPR by breaking down the evidence available in the literature and addressing the reasons behind these discrepancies. We also highlight underexplored areas and key unanswered questions in the field. A better synchronization and integration of methodologies, models, and mechanistic pathways will be crucial to discover the true nature of the TDP-43 and ER stress relationship and, ultimately, to uncover the full therapeutic potential of the UPR.
Highlights
The abnormal distribution, modification, and aggregation of TAR DNA-binding protein 43 (TDP-43) are the pathological hallmarks of a group of neurodegenerative diseases that are collectively known as TDP-43 proteinopathies (Tziortzouda et al, 2021)
All evidence pointed to the dysregulation of B-cell lymphoma gene 2 (Bcl-2)-mediated endoplasmic reticulum (ER) calcium (Ca2+) signaling being responsible for the increase in TDP-43-associated apoptosis since immortalized cells and primary neurons carrying TDP-43-M337V and TDP-43-A382T mutations presented a 50% reduction of luminal ER Ca2 + levels, and delayed Ca2 + flux when compared to TDP-43-wild type (WT) (Mutihac et al, 2015)
The unfolded protein response (UPR) pathways mediated by Protein kinase RNA-like endoplasmic reticulum kinase (PERK), Inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) and Activating transcription factor 6 (ATF6) play a fundamental role in the maintenance of protein homeostasis
Summary
The abnormal distribution, modification, and aggregation of TAR DNA-binding protein 43 (TDP-43) are the pathological hallmarks of a group of neurodegenerative diseases that are collectively known as TDP-43 proteinopathies (Tziortzouda et al, 2021). In these disorders, the nuclear depletion and cytoplasmic accumulation of TDP-43 leads to gain- and loss-of-function abnormalities within neurons by altering a wide range of biological processes including RNA biogenesis, autophagy, the ubiquitin proteasome system (UPS), and axonal transport among others, that determine cell survival (Prasad et al, 2019). A key challenge, is to identify critical targets and pathways mediating neuronal degeneration In this regard, recent evidence suggests that endoplasmic reticulum (ER) stress may play a pivotal role in the development or pathogenesis of TDP-43 proteinopathies (Walker and Atkin, 2011).
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