Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Pharmacological Interventions to Ameliorate Neuropathological Symptoms in a Mouse Model of Lafora Disease. 2562 94

Lafora disease (LD) is a rare adolescent-onset progressive myoclonic epilepsy caused by loss-of-function mutations either in the EPM2A gene encoding laforin or in the EPM2B gene encoding malin. Mouse models with deletion in the Epm2a or the Epm2b gene show intracellular aggregates of polyglucosans (Lafora bodies) and neurological complications that resemble those observed in patients with LD. In the absence of laforin or malin expression, mice also show different degrees of hyperexcitability, as reflected by an enhanced response to the convulsant drug pentylenetetrazol (PTZ). Malin knockout mice treated with 4-phenylbutyric acid (4-PBA) and metformin showed decreased amounts of Lafora bodies and polyubiquitin protein aggregates in the brain, diminished neurodegeneration, and amelioration of some neurological conditions. In this study, we analyzed the action of 4-PBA and metformin treatments on response to PTZ in a malin knockout model of LD. Both treatments decreased seizure susceptibility, bringing about a reduction in both seizure number and length, and eliminated the mortality induced by PTZ. These results show a neuroprotective role of 4-PBA and metformin and extend the beneficial effects reported in the malin knockout model of LD Video abstract: http://links.lww.com/WNR/A411.
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PMID:4-Phenylbutyric acid and metformin decrease sensitivity to pentylenetetrazol-induced seizures in a malin knockout model of Lafora disease. 2818 16