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Publications

Journal Article Ahead of print

PubMed: 42687380 DOI: 10.1016/j.ymthe.2026.09.003

AAV-mediated CBLN1 replacement rescues hereditary ataxia caused by biallelic CBLN1 variants.

Mol Ther

Authors: Tokiwa Yamasak, Wataru Kakegawa, Ayumi Hayashi, Naoko Ogawa, Tetsuya Takano, Keiko Matsuda, Kumi Takatsuto, Mohamed S Abdel-Hamid, Maha S Zaki, Joseph Gleeson, Michisuke Yuzaki

Affiliations

  • Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
  • Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; Center for Human Biology-Microbiota-Quantum Computational Research, Keio University, Tokyo 160-8582, Japan; Department of Life Sciences, Faculty of Science, Gakushuin University, Tokyo 171-8588, Japan.
  • Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; Center for Human Biology-Microbiota-Quantum Computational Research, Keio University, Tokyo 160-8582, Japan.
  • Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Center, Cairo 12622, Egypt.
  • Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Center, Cairo 12622, Egypt.
  • Rady Children's Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; Center for Human Biology-Microbiota-Quantum Computational Research, Keio University, Tokyo 160-8582, Japan.

Abstract

Cbln1 is a secreted synaptic organizer required for parallel fiber-Purkinje cell (PF-PC) synapse integrity, climbing fiber (CF) refinement, and cerebellar motor learning, but has not previously been implicated in human disease. We identified biallelic CBLN1 missense variants (A63P and Y112C) in two unrelated families with early-onset cerebellar ataxia accompanied by oculomotor abnormalities, cerebellar atrophy, and variable cognitive delay. In heterologous cells, both variants showed reduced steady-state protein abundance, impaired maturation through the early secretory pathway, and little or no detectable secretion, resulting in markedly reduced extracellular CBLN1 availability. Consistently, cerebellar granule cells expressing CBLN1-Y112C failed to induce excitatory synapses onto glutamate receptor δ2 (GluD2)-expressing cells in vitro. A knock-in mouse harboring Y112C lacked synaptic Cbln1 and recapitulated key features of Cbln1 deficiency, including disrupted PF-PC synapse organization, persistent CF multi-innervation, impaired PF-PC transmission and long-term depression, and deficits in motor coordination and oculomotor learning. Notably, systemic delivery of an astrocyte-targeted adeno-associated virus expressing wild-type CBLN1 in adult mutant mice restored synaptic CBLN1 localization, cerebellar synaptic function, plasticity, and behavior. These findings establish CBLN1 deficiency as a cause of hereditary ataxia and identify extracellular CBLN1 replacement as a therapeutic strategy for a reversible cerebellar synaptopathy.

MeSH

Cells, Ataxia, Learning, Genetic Therapy, Synapses