Elevation of casein kinase 1ε associated with TDP‐43 and tau pathologies in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by the presence of extracellular amyloid β plaques and intraneuronal neurofibrillary tangles of hyperphosphorylated microtubule‐associated protein tau in the brain. Aggregation of transactive response DNA‐binding protein of 43 kDa (TDP‐43) in the neuronal cytoplasm is another feature of AD. However, how TDP‐43 is associated with AD pathogenesis is unknown. Here, we found that casein kinase 1ε (CK1ε) phosphorylated TDP‐43 at Ser403/404 and Ser409/410. In AD brains, the level of CK1ε was dramatically increased and positively correlated with the phosphorylation of TDP‐43 at Ser403/404 and Ser409/410. Overexpression of CK1ε promoted its cytoplasmic aggregation and suppressed TDP‐43‐promoted tau mRNA instability and tau exon 10 inclusion, leading to an increase of tau and 3R‐tau expressions. Levels of CK1ε and TDP‐43 phosphorylation were positively correlated with the levels of total tau and 3R‐tau in human brains. Furthermore, we observed, in pilot immunohistochemical studies, that the severe tau pathology was accompanied by robust TDP‐43 pathology and a high level of CK1ε. Taken together, our findings suggest that the elevation of CK1ε in AD brain may phosphorylate TDP‐43, promote its cytoplasmic aggregation and suppress its function in tau mRNA processing, leading to acceleration/exacerbation of tau pathology. Thus, the elevation of CK1ε may link TDP‐43 to tau pathogenesis in AD brain.

The Molecular Clock and Neurodegenerative Disease: A Stressful Time

“…Future research is needed to clarify the mechanisms of CK1δ-related accumulation in pathogenic tau plaques, although some work suggests a possible interaction with transactive response DNA-binding protein (TDP-43), another hallmark of neurodegeneration. CK1δ phosphorylates TDP-43 and promote its mislocalization (Nonaka et al, 2014;Gu et al, 2020), aggregating with TDP-43 and tau in granulovacuolar degeneration bodies (GVBs) of the cytoplasm, to promote tau hyperphosphorylation (Ghoshal et al, 1999;Yamazaki et al, 2011). Of note, CK1δ also contributes to neurodegenerative diseases through amyloidosis.…”

The role of DNA damage response in amyotrophic lateral sclerosis

“…In addition, TDP43 cytoplasmic retention can be aggravated by other factors such as ataxin 2 (ATXN2), itself associated with DDR processes [ 65 ], thereby further increasing the risk of developing ALS [ 66 ]. Furthermore, TDP43 mislocalization and GIN accumulation maintain a vicious cycle via casein kinase 1ε (CK1ε) that has been shown to promote cytoplasmic accumulation of TDP43 [ 67 ]. Together with other CK1 isoforms, CK1ε is activated upon GIN build-up and controls several cellular processes linked to DNA damage signalling and repair, including apoptosis and cell cycle checkpoint control ( Figure 4 a) [ 68 ].…”

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

“…However, its dysregulation leads to different pathologies including cancer and neurodegenerative diseases 11 . Recently, inhibition of CK-1, mainly the δ and ε isoforms, has been proposed as a potential treatment for different neurodegenerative diseases including ALS, FTD 9 and Alzheimer's disease 12 .…”

“…They have been proven to decreased TDP-43 phosphorylation both in cellular models and in vivo using a Drosophila transgenic model 11 . Moreover, two of these candidates, named as IGS-2.7 and IGS-2.37, have also shown a decrease on TDP-43 phosphorylation and nuclear localization using a cell-based model of human lymphoblast from FTD patients carrying a progranulin (GRN) mutation 12 . Therefore, our working hypothesis is that inhibitors of CK-1δ able to modulate TDP-43 proteinopathy in vivo, may be a good therapeutic strategy for the severe ALS.…”