Loss of laforin or malin results in increased Drp1 level and concomitant mitochondrial fragmentation in Lafora disease mouse models

Upadhyay, Mamta; Agarwal, Saloni; Bhadauriya, Pratibha; Ganesh, Subramaniam

doi:10.1016/j.nbd.2017.01.002

Cited by 18 publications

(10 citation statements)

References 76 publications

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“…Also, the overexpression of laforin and malin in SH‐SY5Y cells did not affect the translocation of Parkin that occurred upon these treatments, which indicates again that laforin and malin do not play a major role in the regulation of canonical mitophagy signalling pathway. Our results do not support a recent publication which has suggested that translocation of Parkin to mitochondria upon CCCP treatment was dramatically reduced in mouse fibroblasts from Epm2a − / − and Epm2b − / − mice . Perhaps variations in the models employed could account for this difference.…”

Section: Discussioncontrasting

confidence: 99%

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Degradation of altered mitochondria by autophagy is impaired in Lafora disease

et al. 2018

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Lafora disease (LD) is a fatal neurodegenerative disorder caused mostly by mutations in either of two genes encoding laforin and malin. LD is characterized by accumulation of a poorly branched form of glycogen in the cytoplasm of neurons and other cells. We previously reported dysfunctional mitochondria in different LD models. Now, using mitochondrial uncouplers and respiratory chain inhibitors, we have investigated with human fibroblasts a possible alteration in the selective degradation of damaged mitochondria (mitophagy) in LD. By flow cytometry of MitoTracker-labelled cells and measuring the levels of various mitochondrial proteins by western blot, we found in LD fibroblasts a partial impairment in the increased mitochondrial degradation produced by these treatments. In addition, colocalization of mitochondrial and lysosomal markers decreased in LD fibroblasts. All these results are consistent with a partial impairment in the induced autophagic degradation of dysfunctional mitochondria in LD fibroblasts. However, canonical recruitment of Parkin to mitochondria under these conditions remained unaffected in LD fibroblasts, and also in SH-SY5Y cells after malin and laforin overexpression. Neither mitochondrial localization nor protein levels of Bcl-2-like protein 13, another component of the mitophagic machinery that operates under these conditions, were affected in LD fibroblasts. In contrast, although these treatments raised autophagy in both control and LD fibroblasts, this enhanced autophagy was clearly lower in the latter cells. Therefore, the autophagic degradation of altered mitochondria is impaired in LD, which is due to a partial defect in the autophagic response and not in the canonical mitophagy signalling pathways.

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Section: Discussioncontrasting

confidence: 99%

“…No differences were found in cells treated or not with CCCP. mouse fibroblasts from Epm2aÀ/À and Epm2bÀ/À mice [39]. Perhaps variations in the models employed could account for this difference.…”

Section: Discussionmentioning

confidence: 99%

Degradation of altered mitochondria by autophagy is impaired in Lafora disease

et al. 2018

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“…Interestingly, the FBXO7 E3 ligase, which is involved in Parkin-mediated mitophagy can promote mitophagy in similar way and compensate for parkin deficiency (Burchell et al, 2013). This general model may be enriched by other modulators, such as Malin and CHIP which interact with Parkin to enhance its stability and activity (Imai et al, 2002;Upadhyay et al, 2017), and NEDD4L which controls the ubiquitin-dependent degradation of Pink1 and negatively regulates autophagy (Huang et al, 2020), but their role in mitophagy remains to be demonstrated. Mitophagy can also be triggered independently of Parkin/Pink.…”

Section: Emerging Roles Of E3 Ligases In the Control Of Autophagymentioning

confidence: 99%

E3 Ubiquitin Ligases in Neurological Diseases: Focus on Gigaxonin and Autophagy

Lescouzères

Bomont

2020

Front. Physiol.

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Ubiquitination is a dynamic post-translational modification that regulates the fate of proteins and therefore modulates a myriad of cellular functions. At the last step of this sophisticated enzymatic cascade, E3 ubiquitin ligases selectively direct ubiquitin attachment to specific substrates. Altogether, the ∼800 distinct E3 ligases, combined to the exquisite variety of ubiquitin chains and types that can be formed at multiple sites on thousands of different substrates confer to ubiquitination versatility and infinite possibilities to control biological functions. E3 ubiquitin ligases have been shown to regulate behaviors of proteins, from their activation, trafficking, subcellular distribution, interaction with other proteins, to their final degradation. Largely known for tagging proteins for their degradation by the proteasome, E3 ligases also direct ubiquitinated proteins and more largely cellular content (organelles, ribosomes, etc.) to destruction by autophagy. This multi-step machinery involves the creation of double membrane autophagosomes in which engulfed material is degraded after fusion with lysosomes. Cooperating in sustaining homeostasis, actors of ubiquitination, proteasome and autophagy pathways are impaired or mutated in wide range of human diseases. From initial discovery of pathogenic mutations in the E3 ligase encoding for E6-AP in Angelman syndrome and Parkin in juvenile forms of Parkinson disease, the number of E3 ligases identified as causal gene for neurological diseases has considerably increased within the last years. In this review, we provide an overview of these diseases, by classifying the E3 ubiquitin ligase types and categorizing the neurological signs. We focus on the Gigaxonin-E3 ligase, mutated in giant axonal neuropathy and present a comprehensive analysis of the spectrum of mutations and the recent biological models that permitted to uncover novel mechanisms of action. Then, we discuss the common functions shared by Gigaxonin and the other E3 ligases in cytoskeleton architecture, cell signaling and autophagy. In particular, we emphasize their pivotal roles in controlling multiple steps of the autophagy pathway. In light of the various targets and extending functions sustained by a single E3 ligase, we finally discuss the challenge in understanding the complex pathological cascade underlying disease and in designing therapeutic approaches that can apprehend this complexity.

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“…Activation of mTOR in laforin-deficient cells further activated serum/glucocorticoid-induced kinase 1 (SGK1), and suppression of SGK1 activity could lower glycogen accumulation, inhibited mTOR and rescued the autophagy defect (Singh et al, 2013). Defective autophagic flux could lead to inefficient glycophagy and build-up of Lafora bodies that have neurotoxic effects (Duran et al, 2014); additionally, was also associated with impaired mitophagy, increased mitochondrial fragmentation and ROS production, and decreased ATP levels in laforin- and malin-deficient cells (Roma-Mateo et al, 2015; Upadhyay et al, 2017; Lahuerta et al, 2018).…”

Section: The Role Of Autophagy In Glycogen Storage Disordersmentioning

confidence: 99%

Biomedical Implications of Autophagy in Macromolecule Storage Disorders

Palhegyi

Seranova

Dimova

et al. 2019

Front. Cell Dev. Biol.

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An imbalance between the production and clearance of macromolecules such as proteins, lipids and carbohydrates can lead to a category of diseases broadly known as macromolecule storage disorders. These include, but not limited to, neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease associated with accumulation of aggregation-prone proteins, Lafora and Pompe disease associated with glycogen accumulation, whilst lipid accumulation is characteristic to Niemann-Pick disease and Gaucher disease. One of the underlying factors contributing to the build-up of macromolecules in these storage disorders is the intracellular degradation pathway called autophagy. This process is the primary clearance route for unwanted macromolecules, either via bulk non-selective degradation, or selectively via aggrephagy, glycophagy and lipophagy. Since autophagy plays a vital role in maintaining cellular homeostasis, cell viability and human health, malfunction of this process could be detrimental. Indeed, defective autophagy has been reported in a number of macromolecule storage disorders where autophagy is impaired at distinct stages, such as at the level of autophagosome formation, autophagosome maturation or improper lysosomal degradation of the autophagic cargo. Of biomedical relevance, autophagy is regulated by multiple signaling pathways that are amenable to chemical perturbations by small molecules. Induction of autophagy has been shown to improve cell viability and exert beneficial effects in experimental models of various macromolecule storage disorders where the lysosomal functionality is not overtly compromised. In this review, we will discuss the role of autophagy in certain macromolecule storage disorders and highlight the potential therapeutic benefits of autophagy enhancers in these pathological conditions.

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Loss of laforin or malin results in increased Drp1 level and concomitant mitochondrial fragmentation in Lafora disease mouse models

Cited by 18 publications

References 76 publications

Degradation of altered mitochondria by autophagy is impaired in Lafora disease

Degradation of altered mitochondria by autophagy is impaired in Lafora disease

E3 Ubiquitin Ligases in Neurological Diseases: Focus on Gigaxonin and Autophagy

Biomedical Implications of Autophagy in Macromolecule Storage Disorders

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