Early pathogenesis in the adult-onset neurodegenerative disease amyotrophic lateral sclerosis

Brigitte Van Zundert, Pamela Izaurieta, Elsa Fritz, Francisco J. Alvarez

Resultado de la investigación: Contribución a una revistaArtículo

45 Citas (Scopus)


Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by dysfunction and degeneration of motor neurons starting in adulthood. Most of our knowledge about the pathophysiological mechanisms of ALS comes from transgenic mice models that emulate a subgroup of familial ALS cases (FALS), with mutations in the gene encoding superoxide dismutase (SOD1). In the more than 15 years since these mice were generated, a large number of abnormal cellular mechanisms underlying motor neuron degeneration have been identified, but to date this effort has led to few improvements in therapy, and no cure. Here, we consider that this surfeit of mechanisms is best interpreted by current insights that suggest a very early initiation of pathology in motor neurons, followed by a diversity of secondary cascades and compensatory mechanisms that mask symptoms for decades, until trauma and/or aging overloads their protective function. This view thus posits that adult-onset ALS is the consequence of processes initiated during early development. In fact, motor neurons in neonatal mutant SOD mice display important alterations in their intrinsic electrical properties, synaptic inputs and morphology that are accompanied by subtle behavioral abnormalities. We consider evidence that human mutant SOD1 protein in neonatal hSOD1G93A mice instigates motor neuron degeneration by increasing persistent sodium currents and excitability, in turn altering synaptic circuits that control excessive motor neuron firing and leads to excitotoxicity. We also discuss how therapies that are aimed at suppressing abnormal neuronal activity might effectively mitigate or prevent the onset of irreversible neuronal damage in adulthood. J. Cell. Biochem. 113: 3301-3312, 2012.

Idioma originalInglés
Páginas (desde-hasta)3301-3312
Número de páginas12
PublicaciónJournal of Cellular Biochemistry
EstadoPublicada - nov 2012

Áreas temáticas de ASJC Scopus

  • Bioquímica
  • Biología celular
  • Biología molecular

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