Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy <i>in vivo</i>

Kustermann, Monika; Manta, Linda; Paone, Christoph; Kustermann, Jochen; Lausser, Ludwig; Wiesner, Cora; Eichinger, Ludwig M.; Clemen, Christoph S.; Schröder, Rolf; Kestler, Hans A.; Sandri, Marco; Rottbauer, Wolfgang; Just, Steffen

doi:10.1080/15548627.2018.1491491

Cited by 38 publications

(46 citation statements)

References 51 publications

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“…However, VCP R155H/+ mouse muscle did accumulate LGALS3 and had enhance TFEB activity consistent with accumulation of damaged lysosomes; a UBXN6 dependent process. These data are consistent with a recent study that inactivated VCP in the vertebrate model, zebrafish [34]. Loss of VCP caused cardiac and skeletal muscle degeneration with defects in both the ubiquitin-proteasome (UPS) and autophagy [34].…”

Section: Discussionsupporting

confidence: 92%

“…These data are consistent with a recent study that inactivated VCP in the vertebrate model, zebrafish [34]. Loss of VCP caused cardiac and skeletal muscle degeneration with defects in both the ubiquitin-proteasome (UPS) and autophagy [34]. In contrast, targeted inactivation of the VCP cofactor Washc4 in zebrafish caused muscle degeneration, and only autophagic degradation appeared defective [34].…”

Section: Discussionsupporting

confidence: 91%

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VCP maintains lysosomal homeostasis and TFEB activity in differentiated skeletal muscle

et al. 2019

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Differentiated tissue is particularly vulnerable to alterations in protein and organelle homeostasis. The essential protein VCP, mutated in hereditary inclusion body myopathy, amyotrophic lateral sclerosis and frontotemporal dementia, is critical for efficient clearance of misfolded proteins and damaged organelles in dividing cells, but its role in terminally differentiated tissue affected by disease mutations is less clear. To understand the relevance of VCP in differentiated tissue, we inactivated it in skeletal muscle of adult mice. Surprisingly, knockout muscle demonstrated a necrotic myopathy with increased macroautophagic/autophagic proteins and damaged lysosomes. This was not solely due to a defect in autophagic degradation because age-matched mice with muscle inactivation of the autophagy essential protein, ATG5, did not demonstrate a myopathy. Notably, myofiber necrosis was preceded by upregulation of LGALS3/Galectin-3, a marker of damaged lysosomes, and TFEB activation, suggesting early defects in the lysosomal system. Consistent with that, myofiber necrosis was recapitulated by chemical induction of lysosomal membrane permeabilization (LMP) in skeletal muscle. Moreover, TFEB was activated after LMP in cells, but activation and nuclear localization of TFEB persisted upon VCP inactivation or disease mutant expression. Our data identifies VCP as central mediator of both lysosomal clearance and biogenesis in skeletal muscle.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 91%

VCP maintains lysosomal homeostasis and TFEB activity in differentiated skeletal muscle

et al. 2019

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“…Movies of 10–30 seconds were acquired for each sample to show the larval response to the needle touch. For each experiment the number of embryos with adequate response to the touch was converted to a percentage, analysed, and plotted in a bar graph using GraphPad Prism software[ 11 , 42 ].…”

Section: Methodsmentioning

confidence: 99%

Genetic compensation prevents myopathy and heart failure in an in vivo model of Bag3 deficiency

et al. 2020

Self Cite

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Mutations in the molecular co-chaperone Bcl2-associated athanogene 3 (BAG3) are found to cause dilated cardiomyopathy (DCM), resulting in systolic dysfunction and heart failure, as well as myofibrillar myopathy (MFM), which is characterized by protein aggregation and myofibrillar disintegration in skeletal muscle cells. Here, we generated a CRISPR/Cas9-induced Bag3 knockout zebrafish line and found the complete preservation of heart and skeletal muscle structure and function during embryonic development, in contrast to morpholino-mediated knockdown of Bag3. Intriguingly, genetic compensation, a process of transcriptional adaptation which acts independent of protein feedback loops, was found to prevent heart and skeletal muscle damage in our Bag3 knockout model. Proteomic profiling and quantitative real-time PCR analyses identified Bag2, another member of the Bag protein family, significantly upregulated on a transcript and protein level in bag3 -/- mutants. This implied that the decay of bag3 mutant mRNA in homozygous bag3 -/- embryos caused the transcriptional upregulation of bag2 expression. We further demonstrated that morpholino-mediated knockdown of Bag2 in bag3 -/- embryos evoked severe functional and structural heart and skeletal muscle defects, which are similar to Bag3 morphants. However, Bag2 knockdown in bag3 +/+ or bag3 +/- embryos did not result in (cardio-)myopathy. Finally, we found that inhibition of the nonsense-mediated mRNA decay (NMD) machinery by knockdown of upf1 , an essential NMD factor, caused severe heart and skeletal muscle defects in bag3 -/- mutants due to the blockade of transcriptional adaptation of bag2 expression. Our findings provide evidence that genetic compensation might vitally influence the penetrance of disease-causing bag3 mutations in vivo .

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“…As in people with VCP ‐associated FTD, a common feature of the above mutant VCP mice is an increase in protein ubiquitination and the presence of TDP‐43 pathology, suggesting that compromised protein degradation is a consequence of VCP mutations in line with its known function in proteostasis. Indeed, VCP knockdown in zebrafish disrupts both proteasomal‐ and autophagy‐mediated protein degradation . In the murine models TDP‐43 accumulates in the cytosol in VCP‐negative aggregates; in one model TDP‐43 inclusions also contained the stress granule marker TIA‐1 additionally implicating stress granule dynamics in VCP‐mediated TDP‐43 mislocalization .…”

Section: Genetic Models Of Ftdmentioning

confidence: 99%

Review: Modelling the pathology and behaviour of frontotemporal dementia

Solomon

Mitchell

Salcher-Konrad

et al. 2019

Neuropathology Appl Neurobio

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Frontotemporal dementia (FTD) encompasses a collection of clinically and pathologically diverse neurological disorders. Clinical features of behavioural and language dysfunction are associated with neurodegeneration, predominantly of frontal and temporal cortices. Over the past decade, there have been significant advances in the understanding of the genetic aetiology and neuropathology of FTD which have led to the creation of various disease models to investigate the molecular pathways that contribute to disease pathogenesis. The generation of in vivo models of FTD involves either targeting genes with known disease‐causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP‐43 and FUS. This review provides a comprehensive summary of the different in vivo model systems used to understand pathomechanisms in FTD, with a focus on disease models which reproduce aspects of the wide‐ranging behavioural phenotypes seen in people with FTD. We discuss the emerging disease pathways that have emerged from these in vivo models and how this has shaped our understanding of disease mechanisms underpinning FTD. We also discuss the challenges of modelling the complex clinical symptoms shown by people with FTD, the confounding overlap with features of motor neuron disease, and the drive to make models more disease‐relevant. In summary, in vivo models can replicate many pathological and behavioural aspects of clinical FTD, but robust and thorough investigations utilizing shared features and variability between disease models will improve the disease‐relevance of findings and thus better inform therapeutic development.

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Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo

Cited by 38 publications

References 51 publications

VCP maintains lysosomal homeostasis and TFEB activity in differentiated skeletal muscle

VCP maintains lysosomal homeostasis and TFEB activity in differentiated skeletal muscle

Genetic compensation prevents myopathy and heart failure in an in vivo model of Bag3 deficiency

Review: Modelling the pathology and behaviour of frontotemporal dementia

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