Protein Degradation and Quality Control in Cells from Laforin and Malin Knockout Mice

Garyali, Punitee; Segvich, Dyann M.; DePaoli‐Roach, Anna A.; Roach, Peter J.

doi:10.1074/jbc.m114.580167

Cited by 37 publications

(25 citation statements)

References 46 publications

(40 reference statements)

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“…Therefore, we wanted to test if the heat shock-induced clearance of polyubiquitinated proteins is effective in the absence of laforin or malin. Corroborating earlier reports (Aguado et al 2010;Puri et al 2012, Criado et al 2012Singh et al 2013;Garyali et al 2014), we found that cells partially silenced for laforin and malin have higher level of polyubiquitinated proteins, compared to the control (Fig. 3a).…”

Section: Resultssupporting

confidence: 76%

“…Malin and laforin are necessary for autophagic induction and loss of either result in autophagy blockade (Aguado et al 2010;Puri et al 2012, Criado et al 2012Singh et al 2013;Garyali et al 2014). The Neuro2a cells used in the present study also showed a similar effect upon a transient loss of laforin or malin (Fig.…”

Section: Resultssupporting

confidence: 65%

“…The loss of either laforin or malin is known to result in the autophagy blockade (Aguado et al 2010;Puri et al 2012;Criado et al 2012;Singh et al 2013;Garyali et al 2014;Jain et al 2016). One of the intriguing observations of the present study is the contrasting effect on heat shock-induced autophagy induction in the Neuro2a cells deficient for laforin as compared with cells that were deficient for malin.…”

Section: Discussionmentioning

confidence: 34%

“…Laforin and malin are thought to function as a complex and have been shown to play a role in proteolytic processes. These include ubiquitin-proteasome system (Mittal et al 2007;Garyali et al 2009) and autophagy; cells deficient for laforin or malin showed autophagy blockade (Aguado et al 2010;Puri et al 2012;Criado et al 2012;Singh et al 2013;Garyali et al 2014). A direct role for these proteins was also shown in heat shock response; laforin and malin were shown to be required for the activation and nuclear translocation of HSF1 (Sengupta et al 2011).…”

Section: Introductionmentioning

confidence: 95%

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Loss of malin, but not laforin, results in compromised autophagic flux and proteasomal dysfunction in cells exposed to heat shock

Jain

Rai

Mishra

et al. 2017

Cell Stress and Chaperones

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Heat stress to a cell leads to the activation of heat shock response, which is required for the management of misfolded and unfolded proteins. Macroautophagy and proteasome-mediated degradation are the two cellular processes that degrade polyubiquitinated, misfolded proteins. Contrasting pieces of evidence exist on the effect of heat stress on the activation of the above-mentioned degradative pathways. Laforin phosphatase and malin E3 ubiquitin ligase, the two proteins defective in Lafora neurodegenerative disorder, are involved in cellular stress response pathways and are required for the activation of heat shock transcription factorthe heat shock factor 1 (HSF1) -and, consequently, for cellular protection under heat shock. While the role of laforin and malin in the proteolytic pathways is well established, their role in cellular recovery from heat shock was not explored. To address this, we investigated autophagic flux, proteasomal activity, and the level of polyubiquitinated proteins in Neuro2a cells partially silenced for laforin or malin protein and exposed to heat shock. We found that heat shock was able to induce autophagic flux, proteasomal activity and reduce the polyubiquitinated proteins load in the laforin-silenced cells but not in the malin-deficient cells. Loss of malin leads to reduced proteasomal activity in the heat-shocked cells. Taken together, our results suggest a distinct mode of action for laforin and malin in the heat shock-induced proteolytic processes.

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Section: Resultssupporting

confidence: 76%

Section: Resultssupporting

confidence: 65%

Section: Discussionmentioning

confidence: 34%

Section: Introductionmentioning

confidence: 95%

See 2 more Smart Citations

Loss of malin, but not laforin, results in compromised autophagic flux and proteasomal dysfunction in cells exposed to heat shock

Jain

Rai

Mishra

et al. 2017

Cell Stress and Chaperones

View full text Add to dashboard Cite

show abstract

“…However, several reports have connected loss of laforin with decreased autophagy, which could have a role in glycogen disposal (42)(43)(44)(45)(46). We therefore also monitored LC3-II and p62 in muscle samples from the experiment described above (Fig.…”

Section: Role Of Laforin In Glycogen Phosphorylation and Branching Dumentioning

confidence: 99%

Muscle Glycogen Remodeling and Glycogen Phosphate Metabolism following Exhaustive Exercise of Wild Type and Laforin Knockout Mice

Irimia¹,

Tagliabracci

Meyer

et al. 2015

Journal of Biological Chemistry

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Background: Glycogen contains a low level of covalent phosphate that is significantly increased in Lafora disease. Results: Exercise removes phosphate from muscle glycogen, but not in a Lafora disease mouse model. Restoration of glycogen level and structure is much faster than phosphate accumulation. Conclusion: Absence of laforin affects glycogen remodeling. Significance: Glycogen phosphorylation is slow, consistent with the teenage onset of Lafora disease.

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Clinicopathologic Dissociation: Robust Lafora Body Accumulation in Malin KO Mice Without Observable Changes in Home‐Cage Behavior

Krishnan,

Wu,

Mazumder

et al. 2024

J of Comparative Neurology

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Lafora disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age‐dependent manner in all mouse models of LD. In this study, we applied home‐cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin‐deficient LD as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, ∼6–7 months, and ∼12 months of age, malin‐deficient mice (“KO”) and wild‐type (WT) littermates underwent a standardized home‐cage behavioral assessment designed to non‐obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion, and voluntary wheel‐running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across the same timepoints, we identified age‐related nocturnal hypoactivity, diminished sucrose preference, and reduced wheel‐running. Neuropathological examinations in subsets of the same mice revealed expected age‐dependent LB accumulation, gliosis, and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. However, in an in vitro assay of neocortical function, paroxysmal bursts of network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced postictal suppression of movement, feeding, and drinking behavior. Together, these results highlight the clinicopathologic dissociation in a mouse model of LD, where the accrual of LBs may latently modify cortical circuit function and seizure threshold without clinically meaningful changes in home‐cage behavior. Our findings allude to a delay between LB accumulation and neurobehavioral decline in LD: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse.

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Protein Degradation and Quality Control in Cells from Laforin and Malin Knockout Mice

Cited by 37 publications

References 46 publications

Loss of malin, but not laforin, results in compromised autophagic flux and proteasomal dysfunction in cells exposed to heat shock

Loss of malin, but not laforin, results in compromised autophagic flux and proteasomal dysfunction in cells exposed to heat shock

Muscle Glycogen Remodeling and Glycogen Phosphate Metabolism following Exhaustive Exercise of Wild Type and Laforin Knockout Mice

Clinicopathologic Dissociation: Robust Lafora Body Accumulation in Malin KO Mice Without Observable Changes in Home‐Cage Behavior

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