Antagonizing bone morphogenetic protein 4 attenuates disease progression in a rat model of amyotrophic lateral sclerosis

Tomomi Shijo, Hitoshi Warita, Naoki Suzuki, Kensuke Ikeda, Shio Mitsuzawa, Tetsuya Akiyama, Hiroya Ono, Ayumi Nishiyama, Rumiko Izumi, Yasuo Kitajima, Masashi Aoki

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neurodegenerative syndrome characterized by the systemic loss of motor neurons with prominent astrocytosis and microgliosis in the spinal cord and brain. Astrocytes play an essential role in maintaining extracellular microenvironments that surround motor neurons, and are activated by various insults. Growing evidence points to a non-cell autonomous neurotoxicity caused by chronic and sustained astrocytic activation in patients with neurodegenerative diseases, including ALS. However, the mechanisms that underlie the harmful effects of astrocytosis in patients with ALS remain unresolved. We focused on bone morphogenetic proteins as a major soluble factor that promotes astrocytogenesis and its activation in the adult spinal cord. In a transgenic rat model with ALS-linked mutant Cu/Zn superoxide dismutase gene, BMP4 was progressively up-regulated in reactive astrocytes of the spinal ventral horns, whereas the BMP-antagonist noggin was decreased in association with neuronal degeneration. Continuous intrathecal noggin supplementation after disease onset significantly ameliorated motor dysfunction symptoms, neurogenic muscle atrophy, and extended survival of symptomatic ALS model rats, despite lack of deterrence against neuronal death itself. The exogenous noggin inhibited astrocytic hypertrophy, astrocytogenesis, and neuroinflammation by inactivating both Smad1/5/8 and p38 mitogen-activated protein kinase pathways. Moreover, intrathecal infusion of a Bmp4-targeted antisense oligonucleotides and provided selective Bmp4 knockdown in vivo, which suppressed astrocyte and microglia activation, reproducing the aforementioned results by noggin treatment. Collectively, we clarified the involvement of BMP4 in the processes of excessive gliosis that exacerbate the disease progression of the ALS model rats. Our study demonstrated that BMP4, with its downstream signaling, might be a novel therapeutic target for disease-modifying therapies in ALS.

Original languageEnglish
Pages (from-to)164-179
Number of pages16
JournalExperimental Neurology
Volume307
DOIs
Publication statusPublished - 2018 Sep

Keywords

  • ALS
  • Amyotrophic lateral sclerosis
  • Antisense oligonucleotide
  • Astrocyte
  • BMP
  • Bone morphogenetic protein
  • Motor neuron
  • Neuroinflammation
  • Non-cell autonomous
  • SOD1

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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