2. Academic Validation
  3. Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease

Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease

  • Sci Transl Med. 2017 Aug 16;9(403):eaag0394. doi: 10.1126/scitranslmed.aag0394.
Claire E Le Pichon 1,  William J Meilandt 2,  Sara Dominguez 1,  Hilda Solanoy 1,  Han Lin 1,  Hai Ngu 3,  Alvin Gogineni 4,  Arundhati Sengupta Ghosh 1,  Zhiyu Jiang 1,  Seung-Hye Lee 1,  Janice Maloney 1,  Vineela D Gandham 4,  Christine D Pozniak 1,  Bei Wang 1,  Sebum Lee 5,  Michael Siu 6,  Snahel Patel 6,  Zora Modrusan 7,  Xingrong Liu 8,  York Rudhard 9,  Miriam Baca 3,  Amy Gustafson 10,  Josh Kaminker 11,  Richard A D Carano 4,  Eric J Huang 5 12,  Oded Foreman 3,  Robby Weimer 4,  Kimberly Scearce-Levie 1,  Joseph W Lewcock 2
Affiliations

Affiliations

  • 1 Department of Neuroscience, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • 2 Department of Neuroscience, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. lewcock@dnli.com meilandt.william@gene.com.
  • 3 Department of Pathology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • 4 Department of Biomedical Imaging, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • 5 Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 6 Department of Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • 7 Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • 8 Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • 9 In Vitro Pharmacology, Evotec AG, Manfred Eigen Campus, 22419 Hamburg, Germany.
  • 10 Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • 11 Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • 12 Pathology Service 113B, San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
PMID: 28814543 DOI: 10.1126/scitranslmed.aag0394
Abstract

Hallmarks of chronic neurodegenerative disease include progressive synaptic loss and neuronal cell death, yet the cellular pathways that underlie these processes remain largely undefined. We provide evidence that dual leucine zipper kinase (DLK) is an essential regulator of the progressive neurodegeneration that occurs in amyotrophic lateral sclerosis and Alzheimer's disease. We demonstrate that DLK/c-Jun N-terminal kinase signaling was increased in mouse models and human patients with these disorders and that genetic deletion of DLK protected against axon degeneration, neuronal loss, and functional decline in vivo. Furthermore, pharmacological inhibition of DLK activity was sufficient to attenuate the neuronal stress response and to provide functional benefit even in the presence of ongoing disease. These findings demonstrate that pathological activation of DLK is a conserved mechanism that regulates neurodegeneration and suggest that DLK inhibition may be a potential approach to treat multiple neurodegenerative diseases.

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