Heat shock protein Grp78/BiP/HspA5 binds directly to TDP-43 and mitigates toxicity associated with disease pathology

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure or effective treatment in which TAR DNA Binding Protein of 43 kDa (TDP-43) abnormally accumulates into misfolded protein aggregates in affected neurons. It is widely accepted that protein misfolding and aggregation promotes proteotoxic stress. The molecular chaperones are a primary line of defense against proteotoxic stress, and there has been long-standing interest in understanding the relationship between chaperones and aggregated protein in ALS. Of particular interest are the heat shock protein of 70 kDa (Hsp70) family of chaperones. However, defining which of the 13 human Hsp70 isoforms is critical for ALS has presented many challenges. To gain insight into the specific Hsp70 that modulates TDP-43, we investigated the relationship between TDP-43 and the Hsp70s using proximity-dependent biotin identification (BioID) and discovered several Hsp70 isoforms associated with TDP-43 in the nucleus, raising the possibility of an interaction with native TDP-43. We further found that HspA5 bound specifically to the RNA-binding domain of TDP-43 using recombinantly expressed proteins. Moreover, in a Drosophila strain that mimics ALS upon TDP-43 expression, the mRNA levels of the HspA5 homologue (Hsc70.3) were significantly increased. Similarly we observed upregulation of HspA5 in prefrontal cortex neurons from human ALS patients. Finally, overexpression of HspA5 in Drosophila rescued TDP-43-induced toxicity, suggesting that upregulation of HspA5 may have a compensatory role in ALS pathobiology.

Data‐independent acquisition proteomics of cerebrospinal fluid implicates endoplasmic reticulum and inflammatory mechanisms in amyotrophic lateral sclerosis

“…Network analysis also revealed an association of a set of endoplasmic reticulum enriched proteins with disability progression rate, in particular: Endoplasmic reticulum chaperone BiP (HSPA5, BiP or GRP78), calreticulin (CALR), and protein disulfide isomerase 4 (PDIA4), which are all associated with induction of endoplasmic reticulum stress. Endoplasmic reticulum stress is thought to be an important early factor in cellular dysfunction in both sporadic and C9orf72 ALS, with a direct interaction between TDP‐43 and BiP also demonstrated (Dafinca et al., 2016, 2021; Feneberg et al., 2020; François‐Moutal et al., 2022; Pilotto et al., 2022; Sasaki, 2010). Our study therefore provides additional novel data indicating a signature of this endoplasmic reticulum dysfunction is evident in CSF, which may be of importance in understanding prognostic heterogeneity in ALS.…”

The Clinicopathological Significance of BiP/GRP-78 in Breast Cancer: A Meta-Analysis of Public Datasets and Immunohistochemical Detection

“…However, BiP positivity was not correlated with Ki67 index and did not significantly change after treatment, although its subcellular localization was significantly increased in the nucleus. BiP can be directed to the nucleus [ 62 ] where it may play a role in reducing DNA damage-induced apoptosis [ 63 , 64 ], while in amyotrophic lateral sclerosis, it binds to TDP-43 to prevent its misfolding and subsequent toxicity [ 65 ]. Moreover, BiP was shown to molecularly interact with ERα and to be required for gene transcription in the uterus, serving as a hub between ERα-independent and ERα-dependent estrogenic responses [ 12 ].…”

TDP-43 impairs sleep in Drosophila through Ataxin-2 –dependent metabolic disturbance

“…Here, we used Drosophila to assess sleep in protein expression models of human neurodegenerative disease. We found that directed expression of TDP-43, which is an established model for ALS/FTD (24,47,(54)(55)(56)(57), led to severe sleep deficits. Depletion of Ataxin-2 (Atx2), a modifier of TDP-43 toxicity in flies and mice (45,58,59), reversed the TDP-43 sleep phenotype.…”