Autophagic down-regulation in motor neurons remarkably prolongs the survival of ALS mice

Kuo Wei Hsueh, Tzyy Wen Chiou, Shu Fen Chiang, Toru Yamashita, Koji Abe, Cesar V. Borlongan, Paul R. Sanberg, Angelayu Hsuan Huang, Shinn Zong Lin, Horng Jyh Harn

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)


Amyotrophic lateral sclerosis (ALS) is a lethal degenerating disease, characterized by progressive muscular atrophy without any effective treatment. Here, we demonstrated the efficacy of abrograting autophagy in motor neurons (MN) by treatment with n-butylidenephthalide (n-BP) in ALS transgenic mice (SOD1G93A). Pre-symptomatic oral administration of 250 mg/kg/bid n-BP significantly prolonged the survival period (203.9 ± 18.3 days), improved motor function, and attenuated MN loss compared to vehicle control (126.4 ± 7.2 days). This prolonged survival of ALS mice is much more robust than that reported with riluzole (140 days), which is an approved clinical therapy for ALS. The therapeutic mechanism targeted by n-BP involved the autophagic pathway as evidenced by decreased LC3-II expression (a biomarker of autophagy), enhanced mTOR levels, and attenuated autophagic activity, altogether increasing MN survival in a dose-dependent manner. This result was also confirmed by double transgenic mice (SOD1G93A:LC3-GFP) which showed that oral administration of n-BP reduced GFP density and decreased caspase-3 expression. In addition, electron microscopy revealed that n-BP administration not only decreased autophagosome number but also reduced morphological dysfunction of mitochondria. In summary, these results indicate that down-regulation of autophagy activation via n-BP may pose as a therapeutic regimen for ALS and relevant neurodegenerative diseases.

Original languageEnglish
Pages (from-to)152-160
Number of pages9
Publication statusPublished - Sept 1 2016

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience


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