2. Academic Validation
  3. Roflupram alleviates autophagy defects and reduces mutant hSOD1-induced motor neuron damage in cell and mouse models of amyotrophic lateral sclerosis

Roflupram alleviates autophagy defects and reduces mutant hSOD1-induced motor neuron damage in cell and mouse models of amyotrophic lateral sclerosis

  • Neuropharmacology. 2024 Jan 11:109812. doi: 10.1016/j.neuropharm.2023.109812.
Di Huo 1,  Weiwei Liang 2,  Di Wang 1,  Qiaochu Liu 3,  Hongyong Wang 1,  Ying Wang 1,  Chunting Zhang 4,  Chaohua Cong 5,  Xiaoli Su 1,  Xingli Tan 1,  Wenmo Zhang 1,  Ling Han 1,  Dongmei Zhang 1,  Ming Wang 1,  Honglin Feng 6
Affiliations

Affiliations

  • 1 Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, PR China.
  • 2 Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, PR China.
  • 3 Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, PR China.
  • 4 Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei City, Anhui Province, PR China.
  • 5 Department of Neurology, Shanghai JiaoTong University School of Medicine, Shanghai No. 9 People's Hospital, Shanghai, PR China.
  • 6 Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, PR China. Electronic address: fenghonglin186@sina.com.
PMID: 38218579 DOI: 10.1016/j.neuropharm.2023.109812
Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal and incurable disease involving motor neuron (MN) degeneration and is characterized by ongoing myasthenia and amyotrophia in adults. Most ALS patients die of respiratory muscle paralysis after an average of 3-5 years. Defective Autophagy in MNs is considered an important trigger of ALS pathogenesis. Roflupram (ROF) was demonstrated to activate Autophagy in microglial cells and exert protective effects against Parkinson's disease (PD) and Alzheimer's disease (AD). Therefore, our research aimed to investigate the efficacy and mechanism of ROF in treating ALS both in vivo and in vitro. We found that ROF could delay disease onset and prolong the survival of hSOD1-G93A transgenic mice. Moreover, ROF protected MNs in the anterior spinal cord, activated the AMPK/ULK1 signalling pathway, increased autophagic flow, and reduced SOD1 aggregation. In an NSC34 cell line stably transfected with hSOD1-G93A, ROF protected against cellular damage caused by hSOD1-G93A. Moreover, we have demonstrated ROF inhibited gliosis in ALS model mice. Collectively, our study suggested that autophagic inducer ROF is neuroprotective in ALS model and the AMPK/ULK1 signalling pathway is a potential therapeutic target in ALS, which increases autophagic flow and reduces SOD1 aggregation.

Keywords

ALS; Autophagy; Motor neuron; Neuroprotection; Roflupram.

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