Optineurin is potentially associated with TDP‐43 and involved in the pathogenesis of inclusion body myositis

Yamashita, Satoshi; Tawara, Nozomu; Sakaguchi, Hidetsugu; Nakama, Tatsuya; Maeda, Yasushi; Hirano, Teruyuki; Uchino, Makoto; Ando, Yumiko

doi:10.1111/j.1365-2990.2012.01297.x

Cited by 32 publications

(23 citation statements)

References 20 publications

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“…TDP-43 inclusions in sIBM, ALS, and FTLD-TDP tissues partly co-localize with other functionally linked ALS proteins that mediate proteasome or autophagic degradation 54, 55 . Cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Acetylation-induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program

Wang¹,

Wander²,

Yuan

et al. 2017

Nat Commun

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TDP-43 pathology marks a spectrum of multisystem proteinopathies including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and sporadic inclusion body myositis. Surprisingly, it has been challenging to recapitulate this pathology, highlighting an incomplete understanding of TDP-43 regulatory mechanisms. Here we provide evidence supporting TDP-43 acetylation as a trigger for disease pathology. Using cultured cells and mouse skeletal muscle, we show that TDP-43 acetylation-mimics promote TDP-43 phosphorylation and ubiquitination, perturb mitochondria, and initiate degenerative inflammatory responses that resemble sporadic inclusion body myositis pathology. Analysis of functionally linked amyotrophic lateral sclerosis proteins revealed recruitment of p62, ubiquilin-2, and optineurin to TDP-43 aggregates. We demonstrate that TDP-43 acetylation-mimic pathology is potently suppressed by an HSF1-dependent mechanism that disaggregates TDP-43. Our study illustrates bidirectional TDP-43 processing in which TDP-43 aggregation is targeted by a coordinated chaperone response. Thus, activation or restoration of refolding mechanisms may alleviate TDP-43 aggregation in tissues that are uniquely susceptible to TDP-43 proteinopathies.

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“…TDP-43 inclusions in sIBM, ALS, and FTLD-TDP tissues partly co-localize with other functionally linked ALS proteins that mediate proteasome or autophagic degradation 54, 55 . Cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Acetylation-induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program

Wang¹,

Wander²,

Yuan

et al. 2017

Nat Commun

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“…The accumulation of misfolded proteins such as amyloid-like substances and TDP-43 emphasizes the degenerative aspect of the pathophysiological mechanisms of sIBM [21,22]. Moreover, poor responsiveness to immunosuppressants in most cases of sIBM strongly suggests that inflammation does not play a central role in sIBM pathology [23].…”

Section: Discussionmentioning

confidence: 99%

Clinical features of Japanese patients with inclusion body myositis

Hori

Yamashita

Tawara

et al. 2014

Journal of the Neurological Sciences

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“…RVs consist of a number of proteins: cyclin-dependent kinase 5 (CDK5) [7], microtubule-associated protein (MAP) light chain3 (LC3) [8], histone H1 and other nuclear proteins [9], aquaporin-4 (AQP4) [10], O-linked N-acetylglucosamine [11], and optineurin. These proteins colocalize with phosphorylated transactive response DNA binding protein-43 (pTDP-43) in RVs, and the cytoplasm of RV-positive fibers [12]. RVs have been reported to be a by-product of an abnormally induced autophagic process [8], [13]–[15].…”

Section: Introductionmentioning

confidence: 99%

Molecular Markers for Granulovacuolar Degeneration Are Present in Rimmed Vacuoles

et al. 2013

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BackgroundRimmed vacuoles (RVs) are round-oval cytoplasmic inclusions, detected in muscle cells of patients with myopathies, such as inclusion body myositis (IBM) and distal myopathy with RVs (DMRV). Granulovacuolar degeneration (GVD) bodies are spherical vacuoles containing argentophilic and hematoxyphilic granules, and are one of the pathological hallmarks commonly found in hippocampal pyramidal neurons of patients with aging-related neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. These diseases are common in the elderly and share some pathological features. Therefore, we hypothesized that mechanisms of vacuolar formation in RVs and GVD bodies are common despite their role in two differing pathologies. We explored the components of RVs by immunohistochemistry, using antibodies for GVD markers.MethodsSubjects included one AD case, eight cases of sporadic IBM, and three cases of DMRV. We compared immunoreactivity and staining patterns for GVD markers. These markers included: (1) tau-modifying proteins (caspase 3, cyclin-dependent kinase 5 [CDK5], casein kinase 1δ [CK1δ], and c-jun N-terminal kinase [JNK]), (2) lipid raft-associated materials (annexin 2, leucine-rich repeat kinase 2 [LRRK2], and flotillin-1), and (3) other markers (charged multi-vesicular body protein 2B [CHMP2B] and phosphorylated transactive response DNA binding protein-43 [pTDP43]) in both GVD bodies and RVs. Furthermore, we performed double staining of each GVD marker with pTDP43 to verify the co-localization.ResultsGVD markers, including lipid raft-associated proteins and tau kinases, were detected in RVs. CHMP2B, pTDP43, caspase 3, LRRK2, annexin 2 and flotillin-1 were detected on the rim and were diffusely distributed in the cytoplasm of RV-positive fibers. CDK5, CK1δ and JNK were detected only on the rim. In double staining experiments, all GVD markers colocalized with pTDP43 in RVs.ConclusionsThese results suggest that RVs of muscle cells and GVD bodies of neurons share a number of molecules, such as raft-related proteins and tau-modifying proteins.

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Optineurin is potentially associated with TDP‐43 and involved in the pathogenesis of inclusion body myositis

Abstract: These findings suggest that OPTN in cooperation with TDP-43 might be involved in the pathophysiological mechanisms of skeletal muscular degeneration in myopathy with rimmed vacuoles. Further investigation into these mechanisms is therefore warranted.

Cited by 32 publications

References 20 publications

Acetylation-induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program

Acetylation-induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program

Clinical features of Japanese patients with inclusion body myositis

Molecular Markers for Granulovacuolar Degeneration Are Present in Rimmed Vacuoles

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