Casein kinase 1 alpha associates with the tau-bearing lesions of inclusion body myositis

Abstract

Inclusion body myositis and Alzheimer's disease are age-related disorders characterized in part by the appearance of intracellular lesions composed of filamentous aggregates of the microtubuleassociated protein tau. Abnormal tau phosphorylation accompanies tau aggregation and may be an upstream pathological event in both diseases. Enzymes implicated in tau hyperphosphorylation in Alzheimer's disease include members of the casein kinase-1 family of phosphotransferases, a group of structurally related protein kinases that frequently function in tandem with the ubiquitin modification system. To determine whether casein kinase-1 isoforms associate with degenerating muscle fibers of inclusion body myositis, muscle biopsy sections isolated from sporadic disease cases were subjected to double-label fluorescence immunohistochemistry using selective anti-casein kinase 1 and anti-phospho-tau antibodies. Results showed that the alpha isoform of casein kinase 1, but not the delta or epsilon isoforms, stained degenerating muscle fibers in all eight inclusion body myositis cases examined. Staining was almost exclusively localized to phospho-tau bearing inclusions. These findings, which extend the molecular similarities between inclusion body myositis muscle and Alzheimer's disease brain, implicate casein kinase-1 alpha as one of the phosphotransferases potentially involved in tau hyperphosphorylation. KeywordsInclusion body myositis; Alzheimer's disease; tau protein; protein phosphorylation; protein kinases; casein kinase 1; immunohistochemistry Sporadic inclusion body myositis (s-IBM) is a progressive muscle disease that leads to atrophy of specific muscle groups [12]. Characteristic histopathological findings include vacuolar degeneration of muscle fibers and mononuclear cell inflammation [3]. s-IBM muscle also shares pathobiochemical features with affected neurons in Alzheimer's disease (AD), including the accumulation of β-amyloid peptide [4,32] and the formation of intracellular filamentous inclusions composed of the microtubule associated protein tau [5]. In both s-IBM and AD, the tau proteins incorporated into filaments contain elevated stoichiometries of phosphorylation [23,24] and ubiquitination [6,20]. Depending on the sites occupied, tau hyperphosphorylation

Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome

“…Recent studies demonstrated that casein kinase 1␦ also phosphorylates numerous sites of tau in vitro, as GSK-3␤ does (53) and probably in vivo as well (54), suggesting that it may also play a role in tau pathology. By using double-labeled fluorescence immunohistochemistry, casein kinase 1 isoforms were found to associate differentially with neurofibrillary and granulovacuolar degeneration lesions in AD brain (55) and with tau-bearing lesions of inclusion body myositis (56). Therefore, future studies should examine whether Dyrk1A also promotes tau phosphorylation with casein kinase 1.…”

Sporadic inclusion-body myositis: Conformational multifactorial ageing-related degenerative muscle disease associated with proteasomal and lysosomal inhibition, endoplasmic reticulum stress, and accumulation of amyloid-β42 oligomers and phosphorylated tau

“…Several kinases known to phosphorylate-tau [89,93,94] are also accumulated within s-IBM muscle fibers, where they colocalize with p-tau-positive inclusions. These include extracellular signal-regulated kinase (ERK) [95], CDK5 [96], glycogen synthase kinase 3b (GSK-3b) [97] and casein kinase 1 [98]. Additionally, GSK-3b is hyperphosphorylated and activated in s-IBM muscle fibers [71].…”

Sporadic inclusion-body myositis: A degenerative muscle disease associated with aging, impaired muscle protein homeostasis and abnormal mitophagy

“…Several kinases known to phosphorylate tau [69,70] are also accumulated within s-IBM muscle fibers, where they co-localize with p-tau-positive inclusions. These include extracellular signalregulated kinase (ERK), CDK5 (reviewed in [26]), glycogen synthase kinase 3β (GSK-3β), and casein kinase 1 [75]. Also, GSK-3β is hyperphosphorylated and activated in s-IBM muscle fibers [50].…”