2. Academic Validation
  3. Pentosidine modification of neuronal proteins induces dendritic spine enlargement in vitro

Pentosidine modification of neuronal proteins induces dendritic spine enlargement in vitro

  • Biochem Biophys Res Commun. 2025 Dec 31:793:153032. doi: 10.1016/j.bbrc.2025.153032.
Azuna Ozawa 1,  Kazuya Toriumi 2,  Tadayuki Shimada 3,  Akinori Endo 4,  Takuya Tomita 5,  Seiichi Munesue 6,  Yasufumi Tomita 7,  Hidetoshi Takagi 8,  Isabella Supardi Parida 8,  Mitsuhiro Miyashita 9,  Reiko Inagi 10,  Masanari Itokawa 8,  Yasuhiko Yamamoto 6,  Yasushi Saeki 5,  Makoto Arai 8
Affiliations

Affiliations

  • 1 Schizophrenia Research Project, Department of Clinical Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan; Molecular and Cellular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8520, Japan.
  • 2 Schizophrenia Research Project, Department of Clinical Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan. Electronic address: toriumi-kz@igakuken.or.jp.
  • 3 Project for Child Brain, Department of Clinical Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan.
  • 4 Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan.
  • 5 Division of Protein Metabolism, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
  • 6 Departments of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan.
  • 7 Schizophrenia Research Project, Department of Clinical Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 277-8563, Japan.
  • 8 Schizophrenia Research Project, Department of Clinical Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan.
  • 9 Schizophrenia Research Project, Department of Clinical Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan; Unit for Mental Health Promotion, Research Center for Social Science & Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan.
  • 10 Division of Chronic Kidney Disease Pathophysiology and Division of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
PMID: 41274251 DOI: 10.1016/j.bbrc.2025.153032
Abstract

Schizophrenia is a psychiatric disorder characterized by positive and negative symptoms and cognitive dysfunction. Recent clinical studies have identified elevated blood levels of pentosidine (PEN), an advanced glycation end product (AGE), in 40 % of patients with schizophrenia, a subgroup associated with severe cognitive dysfunction and resistance to antipsychotic treatment. However, the biological effects of PEN and its contribution to pathophysiology of schizophrenia remain poorly understood. In this study, we established a novel cellular model that recapitulates intracellular PEN accumulation in mouse primary neurons following treatment with glucuronic acid, a precursor of PEN, identified in patients with schizophrenia. Using this model, we performed comprehensive analyses, including liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics, transcriptomics, and morphological assessments. Our findings revealed that PEN modified intracellular neuronal proteins, including histones and synaptic scaffold proteins such as the synaptic Ras GTPase activating protein 1 (SynGAP). These PEN modifications lead to epigenetic dysregulation and Ras-related activation of the C3 botulinum toxin substrate 1 (Rac1), resulting in enlargement of dendritic spines without changes in spine density. This phenotype is similar to that observed in genetic models of schizophrenia, which are associated with cognitive deficits and synaptic dysfunction. These results identify dendritic spine enlargement as a novel pathophysiological feature associated with PEN accumulation and provide mechanistic insights into treatment-resistant cognitive impairment in this schizophrenia. This cellular model offers a promising platform for the development of targeted therapeutics aimed at PEN-associated synaptic dysfunction.

Keywords

Advanced glycation end product; Glucuronic acid; Pentosidine; Rac1; Schizophrenia; Spine morphology.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15723
    99.86%, Ras抑制剂
    Ras
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