2. Academic Validation
  3. Targeting PGAM5-driven mitochondrial integrated stress response slows ALS progression across subtypes

Targeting PGAM5-driven mitochondrial integrated stress response slows ALS progression across subtypes

  • Neuron. 2026 Jun 17;114(12):2109-2127.e14. doi: 10.1016/j.neuron.2026.02.003.
Zhilong Zheng 1,  Wangju Yang 1,  Zhen Chen 1,  Panpan Chen 2,  Mengdan Tao 3,  Shengda Wang 1,  Bowei Cui 1,  Zeyue Yang 1,  Yanqing Yan 1,  Xiao Han 3,  Yongjie Zhang 4,  Zijian Ren 4,  Xiaoxin Yan 5,  Yueqing Jiang 1,  Jing Wang 1,  Tingyou Li 6,  Yan Liu 7,  Xing Guo 8
Affiliations

Affiliations

  • 1 Department of Neurobiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, Jiangsu, China. Electronic address: [email protected].
  • 3 Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing 211166, Jiangsu, China.
  • 4 Department of Human Anatomy, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, China.
  • 5 Department of Anatomy and Neurobiology, Central South University Xiangya Medical School, Changsha 410013, Hunan, China.
  • 6 Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, Jiangsu, China.
  • 7 Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China. Electronic address: [email protected].
  • 8 Department of Neurobiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Jiangsu Key Laboratory of Molecular Targets and Intervention for Metabolic Diseases, Nanjing Medical University, Nanjing 211166, Jiangsu, China. Electronic address: [email protected].
PMID: 41819100 DOI: 10.1016/j.neuron.2026.02.003
Abstract

Amyotrophic lateral sclerosis (ALS) is genetically and clinically heterogeneous, yet convergent pathogenic mechanisms remain poorly defined. A CRISPR-Cas9 screen identified phosphoglycerate mutase-5 (PGAM5) as a common mediator of ALS pathogenesis. PGAM5 activates the mitochondrial integrated stress response (mtISR) via dephosphorylation of metallopeptidase OMA1 at Ser223 and Ser237, thereby driving neuromuscular junction disruption and motor deficits. We show that PGAM5 is a substrate of valosin-containing protein (VCP) and is consistently elevated in spinal cords from sporadic ALS patients, in human spinal cord organoids derived from sporadic or familial ALS, and in ALS mouse models. The disruption of PGAM5-OMA1 interaction by a selective inhibitor (TAT-PO1) or pharmacological inhibition of PGAM5 with telmisartan suppresses mtISR activation and ameliorates ALS-related phenotypes by reshaping mtISR outputs in a manner distinct from those elicited by activation of translation initiation factor 2B (eIF2B). These findings establish PGAM5 as a convergent and actionable therapeutic target across ALS subtypes.

Keywords

ALS; NMJ; PGAM5; VCP; amyotrophic lateral sclerosis; mitochondrial integrated stress response; mitochondrial phosphatase phosphoglycerate mutase 5; mtISR; neuromuscular junction; valosin-containing protein.

Figures
Products