An iPSC-based neural model of sialidosis uncovers glycolytic impairment-causing presynaptic dysfunction and deregulation of Ca2+ dynamics

Haruki Odaka, Tadahiro Numakawa, Minami Soga, Jun Kido, Shiro Matsumoto, Ryutaro Kajihara, Toshika Okumiya, Naoki Tani, Yuki Tanoue, Takaichi Fukuda, Hirokazu Furuya, Takafumi Inoue, Takumi Era*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


Sialidosis is a neuropathic lysosomal storage disease caused by a deficiency in the NEU1 gene-encoding lysosomal neuraminidase and characterized by abnormal accumulation of undigested sialyl-oligoconjugates in systemic organs including brain. Although patients exhibit neurological symptoms, the underlying neuropathological mechanism remains unclear. Here, we generated induced pluripotent stem cells (iPSCs) from skin fibroblasts with sialidosis and induced the differentiation into neural progenitor cells (NPCs) and neurons. Sialidosis NPCs and neurons mimicked the disease-like phenotypes including reduced neuraminidase activity, accumulation of sialyl-oligoconjugates and lysosomal expansions. Functional analysis also revealed that sialidosis neurons displayed two distinct abnormalities, defective exocytotic glutamate release and augmented α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR)-mediated Ca2+ influx. These abnormalities were restored by overexpression of the wild-type NEU1 gene, demonstrating causative role of neuraminidase deficiency in functional impairments of disease neurons. Comprehensive proteomics analysis revealed the significant reduction of SNARE proteins and glycolytic enzymes in synaptosomal fraction, with downregulation of ATP production. Bypassing the glycolysis by treatment of pyruvate, which is final metabolite of glycolysis pathway, improved both the synaptsomal ATP production and the exocytotic function. We also found that upregulation of AMPAR and L-type voltage dependent Ca2+ channel (VDCC) subunits in disease neurons, with the restoration of AMPAR-mediated Ca2+ over-load by treatment of antagonists for the AMPAR and L-type VDCC. Our present study provides new insights into both the neuronal pathophysiology and potential therapeutic strategy for sialidosis.

Original languageEnglish
Article number105279
JournalNeurobiology of Disease
Publication statusPublished - 2021 May


  • AMPA receptor
  • Exocytosis
  • Glycolysis
  • Lysosomal storage disease
  • Neuraminidase
  • Neurotransmission
  • SNARE protein
  • Sialidosis
  • Voltage dependent Ca channel
  • iPSC

ASJC Scopus subject areas

  • Neurology


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