Trehalose Ameliorates Seizure Susceptibility in Lafora Disease Mouse Models by Suppressing Neuroinflammation and Endoplasmic Reticulum Stress

Sinha, Priyanka; Verma, Bhupender; Ganesh, Subramaniam

doi:10.1007/s12035-020-02170-3

Cited by 33 publications

(27 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It also recapitulates [ 1 ] several pathological features of LD already demonstrated in mouse models of the disease, such as glycogen accumulation, increased apoptotic cell death, neuroinflammation and autophagy abnormalities. Using trehalose, an autophagy stimulator as an example of one of the repurposed drugs tested in LD [ 38 ], we also observed in larvae the rescue of the motor and epileptic impairment and demonstrated that our model represents a valid tool for LD pharmacological screening.…”

Section: Introductionmentioning

confidence: 81%

“…Early dietary supplementation with the autophagy flux modulator trehalose ameliorated PTZ-induced seizure susceptibility in laforin-deficient mice [ 38 ] without acting on LBs. In zebrafish we corroborated these data: Early administration of trehalose reduced neuronal excitability and the frequency of spontaneous seizures and rescued the motor impairment, offering further support to its clinical use in children with LD.…”

Section: Discussionmentioning

confidence: 99%

“…Although there exists a rare canine form of LD [ 28 , 29 ], rodents are usually used for studying the disease pathomechanisms and for drug screening purposes. To date, several drugs have been repurposed for LD and tested in mouse models, such as metformin and 4-phenylbutyric acid [ 35 ], sodium selenate [ 36 ], dexamethasone [ 37 ] and trehalose [ 38 ]. Given the growing possibilities of drug repurposing in storage disorders such as LD and the necessity to screen new small molecules, there is a need for feasible and more suitable disease models that allow faster results and reducing the costs for pharmacological testing.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Trehalose Treatment in Zebrafish Model of Lafora Disease

Vecchia

Ogi

Licitra

et al. 2022

IJMS

View full text Add to dashboard Cite

Mutations in the EPM2A gene encoding laforin cause Lafora disease (LD), a progressive myoclonic epilepsy characterized by drug-resistant seizures and progressive neurological impairment. To date, rodents are the only available models for studying LD; however, their use for drug screening is limited by regulatory restrictions and high breeding costs. To investigate the role of laforin loss of function in early neurodevelopment, and to screen for possible new compounds for treating the disorder, we developed a zebrafish model of LD. Our results showed the epm2a−/− zebrafish to be a faithful model of LD, exhibiting the main disease features, namely motor impairment and neuronal hyperexcitability with spontaneous seizures. The model also showed increased inflammatory response and apoptotic death, as well as an altered autophagy pathway that occurs early in development and likely contributes to the disease progression. Early administration of trehalose was found to be effective for rescuing motor impairment and neuronal hyperexcitability associated with seizures. Our study adds a new tool for investigating LD and might help to identify new treatment opportunities.

show abstract

Section: Introductionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Trehalose Treatment in Zebrafish Model of Lafora Disease

Vecchia

Ogi

Licitra

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…[7] The suppression of neuro-inflammation post trehalose intervention has also been reported. [46] Here we found that dAGEs also triggered neuroinflammation in female APP/PS1 mice, yet trehalose relieved it, suggesting that the improved cognitive function post trehalose intervention in AGEs fed female mice might also be partially owing to improved neuro-inflammation. It should also be mentioned that although previous findings reported that AGEs could trigger accumulations of A𝛽 plaques, [9] no notable alterations of key protein involved in A𝛽 generation and production including IDE, ADAM10, BACE1, and cathepsin B were observed in our study.…”

Section: Discussionmentioning

confidence: 62%

Sex‐Specific Neurotoxicity of Dietary Advanced Glycation End Products in APP/PS1 Mice and Protective Roles of Trehalose by Inhibiting Tau Phosphorylation via GSK‐3β‐TFEB

Zhou

Luo

Zhai

et al. 2021

Molecular Nutrition Food Res

View full text Add to dashboard Cite

ScopeIt remains unclear whether dietary advanced glycation end products (dAGEs)‐induced cognitive impairment is sex‐dependent. Trehalose may antagonize dAGEs‐induced neurotoxicity via glycogen synthase kinase‐3 beta (GSK3β)‐transcription factor EB (TFEB) signaling.Methods and ResultsThe sex‐specific neurotoxicity of dAGEs and the protective role of trehalose are investigated both in vivo and in vitro. Both sexes of APP/PS1 mice are divided into three groups: that is, control, dAGEs, and dAGEs supplemented with trehalose. SHSY‐5Y cells incubated with AGE‐BSA and trehalose are also utilized. Dietary AGEs impair cognitive function only in female mice, which is restored by trehalose. Trehalose upregulates phosphorylated‐GSK3β serine9 (p‐GSK3β ser9), TFEB and transient receptor potential mucolipin 1, ADAM10, oligosaccharyl transferase‐48, estrogen receptor α and induces TFEB nuclear translocation in hippocampus, elevates IDE and ERβ in cortex, while reduces p‐tau ser396&404, CDK5, cathepsin B, and glial fibrillary acidic protein in hippocampus. Trehalose elevates p‐GSK3β ser9, induces TFEB nuclear translocation, consequently reverses AGE‐BSA‐induced tau phosphorylation in vitro.ConclusionsFemale mice are more susceptible to the deleterious effects of dAGEs on cognitive function, which may be owing to its regulation on ERβ. Trehalose can strongly reverse dAGEs‐induced tau phosphorylation by potentiating TFEB nuclear translocation via inhibiting GSK‐3β.

show abstract

“…Transcriptomic analyses showed that 94% of genes upregulated in the disease encode proteins of inflammatory and immune system pathways [14]. Finally, downregulation of GYS1 activity by transgenic or other means resulting in PB reductions partially corrected these abnormalities [15][16][17][18][19][20]. Of the several hundred immune system genes shown to be dysregulated in the transcriptomic studies, a subset (less than 10) was tested and confirmed by qRT-PCR, of which several were shown to already be overexpressed at earlier stages of the disease [14,20].…”

Section: Effects On Pb-associated Immune Activationmentioning

confidence: 99%

TargetingGys1with AAV‐SaCas9 decreases pathogenic polyglucosan bodies and neuroinflammation in Adult Polyglucosan Body and Lafora disease mouse models

Gumusgoz

Guisso

Kasiri

et al. 2021

Preprint

View full text Add to dashboard Cite

Many adult and most childhood neurological diseases have a genetic basis. CRISPR/Cas9 biotechnology holds great promise in neurological therapy, pending the clearance of major delivery, efficiency and specificity hurdles. We apply CRISPR/Cas9 genome editing in its simplest modality, namely inducing gene sequence disruption, to one adult and one pediatric disease. Adult polyglucosan body disease is a neurodegenerative disease resembling amyotrophic lateral sclerosis. Lafora disease is a severe late childhood onset progressive myoclonus epilepsy. The pathogenic insult in both is formation in the brain of glycogen with overlong branches, which precipitates and accumulates into polyglucosan bodies that drive neuroinflammation and neurodegeneration. We packaged Staphylococcus aureus Cas9 and a guide RNA targeting the glycogen synthase gene Gys1 responsible for brain glycogen branch elongation in AAV9 virus, which we delivered by neonatal intracerebroventricular injection to one mouse model of adult polyglucosan body disease and two mouse models of Lafora disease. This resulted, in all three models, in editing of approximately 17% of Gys1 alleles and a similar extent of reduction of Gys1 mRNA across the brain. The latter led to approximately 50% reductions of GYS1 protein, of abnormal glycogen accumulation and of polyglucosan bodies, as well as corrections of neuroinflammatory markers in all three models. Our work represents proof of principle for virally-delivered CRISPR/Cas9 neurotherapeutics in an adult-onset (adult polyglucosan body) and a childhood-onset (Lafora) neurological diseases.

show abstract

Trehalose Ameliorates Seizure Susceptibility in Lafora Disease Mouse Models by Suppressing Neuroinflammation and Endoplasmic Reticulum Stress

Cited by 33 publications

References 76 publications

Trehalose Treatment in Zebrafish Model of Lafora Disease

Trehalose Treatment in Zebrafish Model of Lafora Disease

Sex‐Specific Neurotoxicity of Dietary Advanced Glycation End Products in APP/PS1 Mice and Protective Roles of Trehalose by Inhibiting Tau Phosphorylation via GSK‐3β‐TFEB

TargetingGys1with AAV‐SaCas9 decreases pathogenic polyglucosan bodies and neuroinflammation in Adult Polyglucosan Body and Lafora disease mouse models

Contact Info

Product

Resources

About