Molecular Neurobiology

, Volume 53, Issue 2, pp 1296–1309 | Cite as

Pharmacological Interventions to Ameliorate Neuropathological Symptoms in a Mouse Model of Lafora Disease

  • Arnaud Berthier
  • Miguel Payá
  • Ana M. García-Cabrero
  • Maria Inmaculada Ballester
  • Miguel Heredia
  • José M. Serratosa
  • Marina P. Sánchez
  • Pascual SanzEmail author


Lafora disease (LD, OMIM 254780) is a rare fatal neurodegenerative disorder that usually occurs during childhood with generalized tonic-clonic seizures, myoclonus, absences, drop attacks, or visual seizures. Unfortunately, at present, available treatments are only palliatives and no curative drugs are available yet. The hallmark of the disease is the accumulation of insoluble polyglucosan inclusions, called Lafora bodies (LBs), within the neurons but also in heart, muscle, and liver cells. Mouse models lacking functional EPM2A or EPM2B genes (the two major loci related to the disease) recapitulate the Lafora disease phenotype: they accumulate polyglucosan inclusions, show signs of neurodegeneration, and have a dysregulation of protein clearance and endoplasmic reticulum stress response. In this study, we have subjected a mouse model of LD (Epm2b−/−) to different pharmacological interventions aimed to alleviate protein clearance and endoplasmic reticulum stress. We have used two chemical chaperones, trehalose and 4-phenylbutyric acid. In addition, we have used metformin, an activator of AMP-activated protein kinase (AMPK), as it has a recognized neuroprotective role in other neurodegenerative diseases. Here, we show that treatment with 4-phenylbutyric acid or metformin decreases the accumulation of Lafora bodies and polyubiquitin protein aggregates in the brain of treated animals. 4-Phenylbutyric acid and metformin also diminish neurodegeneration (measured in terms of neuronal loss and reactive gliosis) and ameliorate neuropsychological tests of Epm2b−/− mice. As these compounds have good safety records and are already approved for clinical uses on different neurological pathologies, we think that the translation of our results to the clinical practice could be straightforward.


Lafora disease Polyglucosan accumulation Metformin 4-Phenylbutyric acid Trehalose Pharmacological intervention 



AMP-activated protein kinase


Lafora bodies


Lafora disease


4-Phenylbutyric acid


Sodium dodecyl sulfate polyacrylamide gel electrophoresis



We want to thank Carla Rubio-Villena and Maria Adelaida Garcia-Gimeno for their help in the analyses of glycogen-related enzymes. This work was supported by grants from the Spanish Ministry of Education and Science (SAF2011-27442), Fundació La Marato de TV3 (ref. 100130), and an ACCI2012 action from CIBERER. A.B.. holds a postdoctoral fellowship from the Program “Junta para la Ampliación de Estudios” (JAE-Doc) co-funded by the European Social Fund (ESF).

Supplementary material

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Arnaud Berthier
    • 1
  • Miguel Payá
    • 2
  • Ana M. García-Cabrero
    • 3
  • Maria Inmaculada Ballester
    • 1
  • Miguel Heredia
    • 1
  • José M. Serratosa
    • 3
  • Marina P. Sánchez
    • 3
  • Pascual Sanz
    • 1
    Email author
  1. 1.Instituto de Biomedicina de Valencia (CSIC)Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)ValenciaSpain
  2. 2.Departamento de Farmacología, Facultad de FarmaciaUniversidad de Valencia and Centro de Reconocimiento Molecular y Desarrollo Tecnológico (IDM)ValenciaSpain
  3. 3.Fundación Jimenez Diaz and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)MadridSpain

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