Chronic infusion of SOD1G93A astrocyte-secreted factors induces spinal motoneuron degeneration and neuromuscular dysfunction in healthy rats

Uri N. Ramírez-Jarquín, Fabiola Rojas, Brigitte van Zundert, Ricardo Tapia

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease and studies in vitro show that motoneuron degeneration is triggered by non-cell-autonomous mechanisms. However, whether soluble toxic factor(s) released by mutant superoxide dismutase 1 (SOD1) expressing astrocytes induces death of motoneurons and leads to motor dysfunction in vivo is not known. To directly test this, healthy adult rats were treated with conditioned media derived from primary mouse astrocytes (ACM) that express human (h) SOD1G93A (ACM-hG93A) via chronic osmotic pump infusion in the lumbar spinal cord. Controls included ACM derived from transgenic mice expressing hSOD1WT (ACM-hWT) or non-transgenic mouse SOD1WT (ACM-WT) astrocytes. Rats chronically infused with ACM-hG93A started to develop motor dysfunction at 8 days, as measured by rotarod performance. Additionally, immunohistochemical analyses at day 16 revealed reactive astrogliosis and significant loss of motoneurons in the ventral horn of the infused region. Controls did not show significant motor behavior alterations or neuronal damage. Thus, we demonstrate that factors released in vitro from astrocytes derived from ALS mice cause spinal motoneuron death and consequent neuromuscular dysfunction in vivo.

Original languageEnglish
Pages (from-to)2610-2615
Number of pages6
JournalJournal of Cellular Physiology
Volume232
Issue number10
DOIs
Publication statusPublished - Oct 2017

Keywords

  • ALS
  • excitotoxicity
  • motoneuron
  • soluble toxic factors

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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