Mice overexpressing lamin B1 in oligodendrocytes recapitulate the age-dependent motor signs, but not the early autonomic cardiovascular dysfunction of autosomal-dominant leukodystrophy (ADLD)

V. Lo Martire, Sara Alvente, Stefano Bastianini, Chiara Berteotti, Cristiano Bombardi, Giovanna Calandra-Buonaura, Sabina Capellari, Gary Cohen, Pietro Cortelli, Laura Gasparini, Quasar Padiath, Alice Valli, Giovanna Zoccoli, Alessandro Silvani

Research output: Contribution to journalArticle

Abstract

Autosomal dominant leukodystrophy (ADLD) is a rare adult-onset demyelinating disease caused by overexpression of lamin B1, a nuclear lamina filament. Early autonomic dysfunction involving the cardiovascular system before progressive somatic motor dysfunction is a striking feature of most cases of ADLD. In the Plp-FLAG-LMNB1 transgenic mouse model, lamin B1 overexpression in oligodendrocytes elicits somatic motor dysfunction and neuropathology akin to ADLD. Here, we investigate whether Plp-FLAG-LMNB1 mice also develop autonomic cardiovascular dysfunction before or after somatic motor dysfunction. We find that Plp-FLAG-LMNB1 mice have preserved cardiovascular responses to changes in wake-sleep state and ambient temperature and normal indexes of autonomic modulation at 37–42 weeks of age despite a progressive somatic motor dysfunction, which includes impairments of walking ability (the ability to walk on a narrow path was impaired in 80% of mice at 34–38 weeks of age) and subtle breathing derangements. Only late in the development of the disease phenotype did Plp-FLAG-LMNB1 mice develop a structural deficit of sympathetic noradrenergic fibers, with a 38% decrease in fiber profiles in the kidneys at 44–47 weeks of age. We demonstrate that while the Plp-FLAG-LMNB1 mouse model recapitulates the age-dependent motor dysfunction of ADLD, it does not show signs of early autonomic cardiovascular dysfunction, raising the possibility that oligodendrocyte dysfunction may not be sufficient to cause the full spectrum of clinical features present in ADLD.

Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalExperimental Neurology
Volume301
DOIs
Publication statusPublished - Mar 1 2018

Keywords

  • Arterial pressure
  • Breathing
  • Gait
  • Heart rate
  • Lamin
  • Leukodystrophy
  • Mice
  • Oligodendrocyte
  • Sleep
  • Sympathetic

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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