Trehalose Treatment in Zebrafish Model of Lafora Disease

Abstract

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.

Glial Contributions to Lafora Disease: A Systematic Review

“…The early activation of glial cells has also been observed in a laforin-deficient zebrafish model [ 14 ], while the upregulation of gfap also confirmed astrocyte involvement in epm2a −/− zebrafish larvae [ 14 ]. Furthermore, the analysis of inflammatory and glia-specific genes suggests that differently polarized glial populations may coexist in the zebrafish LD model.…”

“…Five additional studies were selected by checking the references of the identified relevant papers. A total of 35 studies were then identified for inclusion in the current review [ 10 , 12 , 14 , 18 , 21 , 22 , 23 , 38 , 39 , 40 , 41 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ].…”

“…Interesting results emerged from the larval zebrafish model of LD [ 14 ]. Up to 5-day-old laforin-deficient zebrafish larvae do not develop PBs but show several metabolic/histopathological alterations, including altered autophagy and neuroinflammation, and are already epileptic, suggesting a role of alternative factors to PBs in neuroinflammation in the epileptic phenotype, at least in zebrafish [ 14 ].…”

“…In addition to alterations in glycogen metabolism, animal models of LD revealed alterations in several metabolic and molecular pathways [ 6 , 7 ] that may influence each other and play a role in the disease [ 6 , 7 ]. These include, in particular, the alteration of autophagy [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ] and the ubiquitin–proteasome system [ 15 , 16 , 17 ], the impairment of the heat shock response [ 16 , 18 ], increased oxidative stress, and mitochondrial dysfunction [ 19 , 20 ].…”

“…In the recent years, neuroinflammation has also emerged as a key histopathological feature in animal models of LD [ 14 , 21 , 22 , 23 ]. Although, neuroinflammation begins as a defensive response [ 24 ], sustained inflammatory responses that involve microglia and astrocytes are detrimental and can contribute to neurodegeneration [ 25 , 26 ].…”