title: Pharmacological Interventions to Ameliorate Neuropathological Symptoms in a Mouse Model of Lafora Disease.
abstract: 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.
authors: Instituto de Biomedicina de Valencia (CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010, Valencia, Spain.
authors: Arnaud
authors: A
authors: Berthier
authors: Departamento de Farmacología, Facultad de Farmacia, Universidad de Valencia and Centro de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), 46100, Valencia, Spain.
authors: Miguel
authors: M
authors: Payá
authors: Fundación Jimenez Diaz and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040, Madrid, Spain.
authors: Ana M
authors: AM
authors: García-Cabrero
authors: Instituto de Biomedicina de Valencia (CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010, Valencia, Spain.
authors: Maria Inmaculada
authors: MI
authors: Ballester
authors: Instituto de Biomedicina de Valencia (CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010, Valencia, Spain.
authors: Miguel
authors: M
authors: Heredia
authors: Fundación Jimenez Diaz and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040, Madrid, Spain.
authors: José M
authors: JM
authors: Serratosa
authors: Fundación Jimenez Diaz and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040, Madrid, Spain.
authors: Marina P
authors: MP
authors: Sánchez
authors: Instituto de Biomedicina de Valencia (CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010, Valencia, Spain. sanz@ibv.csic.es.
authors: Pascual
authors: P
authors: Sanz
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D005911:Gliosis / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D005936:Glucans / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D002479:Inclusion Bodies / Q000187:drug effects / Q000378:metabolism; D020192:Lafora Disease / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology* / Q000503:physiopathology; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D009483:Neuropsychological Tests; D010654:Phenylbutyrates / Q000494:pharmacology / Q000627:therapeutic use; D066329:Protein Aggregates / Q000187:drug effects; D014199:Trehalose / Q000494:pharmacology / Q000627:therapeutic use; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000378:metabolism
chemical_list: D005936:Glucans; D010654:Phenylbutyrates; D066329:Protein Aggregates; D057149:Ubiquitinated Proteins; C075773:4-phenylbutyric acid; C083094:polyglucosan; D008687:Metformin; D014199:Trehalose; C572596:NHLRC1 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: 4-Phenylbutyric acid; Lafora disease; Metformin; Pharmacological intervention; Polyglucosan accumulation; Trehalose
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