title: Postnatal proteasome inhibition induces neurodegeneration and cognitive deficiencies in adult mice: a new model of neurodevelopment syndrome.
abstract: Defects in the ubiquitin-proteasome system have been related to aging and the development of neurodegenerative disease, although the effects of deficient proteasome activity during early postnatal development are poorly understood. Accordingly, we have assessed how proteasome dysfunction during early postnatal development, induced by administering proteasome inhibitors daily during the first 10 days of life, affects the behaviour of adult mice. We found that this regime of exposure to the proteasome inhibitors MG132 or lactacystin did not produce significant behavioural or morphological changes in the first 15 days of life. However, towards the end of the treatment with proteasome inhibitors, there was a loss of mitochondrial markers and activity, and an increase in DNA oxidation. On reaching adulthood, the memory of mice that were injected with proteasome inhibitors postnatally was impaired in hippocampal and amygdala-dependent tasks, and they suffered motor dysfunction and imbalance. These behavioural deficiencies were correlated with neuronal loss in the hippocampus, amygdala and brainstem, and with diminished adult neurogenesis. Accordingly, impairing proteasome activity at early postnatal ages appears to cause morphological and behavioural alterations in adult mice that resemble those associated with certain neurodegenerative diseases and/or syndromes of mental retardation.
authors.affiliation: Departamento de Fisiología, Anatomía y Biología Celular, Universidad Pablo de Olavide, Sevilla, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Romero-Granados
authors.forename: Ángela
authors.initials: Á
authors.lastname: Fontán-Lozano
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Aguilar-Montilla
authors.forename: Ángel Manuel
authors.initials: ÁM
authors.lastname: Carrión
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D001259:Ataxia / Q000150:complications / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000150:complications* / Q000503:physiopathology; D004247:DNA / Q000378:metabolism; D003863:Depression / Q000150:complications / Q000503:physiopathology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007976:Leupeptins / Q000008:administration & dosage / Q000494:pharmacology; D008568:Memory / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000150:complications* / Q000503:physiopathology; D009420:Nervous System / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology*; D010084:Oxidation-Reduction / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D057149:Ubiquitinated Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D007976:Leupeptins; D061988:Proteasome Inhibitors; D057149:Ubiquitinated Proteins; D004247:DNA; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde