Cereblon Regulates the Proteotoxicity of Tau by Tuning the Chaperone Activity of DNAJA1

Abstract

Protein aggregation can induce explicit neurotoxic events that trigger a number of presently untreatable neurodegenerative disorders. Chaperones, on the other hand, play a neuroprotective role because of their ability to unfold and refold abnormal proteins. The progressive nature of neurotoxic events makes it important to discover endogenous factors that affect pathologic and molecular phenotypes of neurodegeneration in animal models. Here, we identified microtubule-associated protein tau, and chaperones Hsp70 (heat shock protein 70) and DNAJA1 (DJ2) as endogenous substrates of cereblon (CRBN), a substrate-recruiting subunit of cullin4-RING-E3-ligase. This recruitment results in ubiquitin-mediated degradation of tau, Hsp70, and DJ2. Knocking out CRBN enhances the chaperone activity of DJ2, resulting in decreased phosphorylation and aggregation of tau, improved association of tau with microtubules, and reduced accumulation of pathologic tau across brain. Functionally abundant DJ2 could prevent tau aggregation induced by various factors like okadaic acid and heparin. Depletion of CRBN also decreases the activity of tau-kinases including GSK3a/b, ERK, and p38. Intriguingly, we found a high expression of CRBN and low levels of DJ2 in neuronal tissues of 5XFAD and APP knock-in male mouse models of Alzheimer's disease. This implies that CRBN-mediated DJ2/Hsp70 pathway may be compromised in neurodegeneration. Being one of the primary pathogenic events, elevated CRBN can be a contributing factor for tauopathies. Our data provide a functional link between CRBN and DJ2/Hsp70 chaperone machinery in abolishing the cytotoxicity of aggregation-prone tau and suggest that Crbn 2/2 mice serve as an animal model of resistance against tauopathies for further exploration of the molecular mechanisms of neurodegeneration.

Damage to the Locus Coeruleus Alters the Expression of Key Proteins in Limbic Neurodegeneration

“…Recently, a remarkable effect of HSP70 in promoting memory formation was reported [133]. Specifically, a recent manuscript by Akber (2021) [134] indicates that HSP70 is a key protein used to protect against deleterious effects induced by p-Tau, which enhances the dual effects of LC-NE axons in modulating the amount of these proteins within limbic areas, as evidenced in the present manuscript. The loss of p62 appears to have a significant value for the onset of neurodegeneration.…”

The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity

“…In parallel, another study tested HSP40 effects on the AD-associated protein tau showing that overexpression of DnaJA1 can favor both tau clearance and stabilization dependent on Hsp70 levels in M17 neuroblastoma cells (Abisambra et al, 2012). A recent study reported similar findings, whereby inducing DnaJA1 activity by CRBN (endogenous substrate of cerebelon) downregulation decreased phosphorylation and aggregation of tau, which was detected in vivo and in vitro (Akber et al, 2021). Furthermore, Abisambra et al also demonstrated DnaJA1-induced polyQ clearance, while alpha-synuclein stability was unaffected in a model of Parkinson's disease.…”

The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls

“…Our findings may therefore help to reconcile these inconsistencies as CB 1 Rs reduce glutamate release (Piomelli, 2003 ) and may also activate BK Ca channels under certain conditions (Stumpff et al, 2005 ; Romano and Lograno, 2006 ; López-Dyck et al, 2017 ). Furthermore, CRBN-KO mice show a resilient phenotype towards stress (Akber et al, 2022 ; Park et al, 2022 ) and the pathological aggregation of Tau, a hallmark of tauopathies as Alzheimer’s disease (Akber et al, 2021 ). Facilitation of CB 1 R signalling also protects against acute and chronic stress, and chronic stress consistently downregulates CB 1 R (Morena et al, 2016 ).…”