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Mature neurons from iPSCs unveil neurodegeneration-related pathways in mucopolysaccharidosis type II: GSK-3ß inhibition for therapeutic potential.
Chen, Tzu-Yu; Lin, Shuan-Pei; Huang, De-Fong; Huang, Hsien-Sung; Tsai, Feng-Chiao; Lee, Li-Jen; Lin, Hsiang-Yu; Huang, Hsiang-Po.
Afiliación
  • Chen TY; Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan.
  • Lin SP; Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.
  • Huang DF; Department of Pediatrics, MacKay Memorial Hospital, Taipei, Taiwan.
  • Huang HS; Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan.
  • Tsai FC; Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan.
  • Lee LJ; Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan.
  • Lin HY; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
  • Huang HP; Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan.
Cell Death Dis ; 15(4): 302, 2024 Apr 29.
Article en En | MEDLINE | ID: mdl-38684682
ABSTRACT
Mucopolysaccharidosis (MPS) type II is caused by a deficiency of iduronate-2-sulfatase and is characterized by the accumulation of glycosaminoglycans (GAGs). Without effective therapy, the severe form of MPS II causes progressive neurodegeneration and death. This study generated multiple clones of induced pluripotent stem cells (iPSCs) and their isogenic controls (ISO) from four patients with MPS II neurodegeneration. MPS II-iPSCs were successfully differentiated into cortical neurons with characteristic biochemical and cellular phenotypes, including axonal beadings positive for phosphorylated tau, and unique electrophysiological abnormalities, which were mostly rescued in ISO-iPSC-derived neurons. RNA sequencing analysis uncovered dysregulation in three major signaling pathways, including Wnt/ß-catenin, p38 MAP kinase, and calcium pathways, in mature MPS II neurons. Further mechanistic characterization indicated that the dysregulation in calcium signaling led to an elevated intracellular calcium level, which might be linked to compromised survival of neurons. Based on these dysregulated pathways, several related chemicals and drugs were tested using this mature MPS II neuron-based platform and a small-molecule glycogen synthase kinase-3ß inhibitor was found to significantly rescue neuronal survival, neurite morphology, and electrophysiological abnormalities in MPS II neurons. Our results underscore that the MPS II-iPSC-based platform significantly contributes to unraveling the mechanisms underlying the degeneration and death of MPS II neurons and assessing potential drug candidates. Furthermore, the study revealed that targeting the specific dysregulation of signaling pathways downstream of GAG accumulation in MPS II neurons with a well-characterized drug could potentially ameliorate neuronal degeneration.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mucopolisacaridosis II / Células Madre Pluripotentes Inducidas / Glucógeno Sintasa Quinasa 3 beta / Neuronas Límite: Humans Idioma: En Revista: Cell Death Dis Año: 2024 Tipo del documento: Article País de afiliación: Taiwán

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mucopolisacaridosis II / Células Madre Pluripotentes Inducidas / Glucógeno Sintasa Quinasa 3 beta / Neuronas Límite: Humans Idioma: En Revista: Cell Death Dis Año: 2024 Tipo del documento: Article País de afiliación: Taiwán