Novel Drug Candidates Improve Ganglioside Accumulation and Neural Dysfunction in GM1 Gangliosidosis Models with Autophagy Activation.

Ryutaro Kajihara,Takumi Era,Yuji Yaginuma,Hirokazu Furuya,Seiji Inui,Haruki Odaka,Tadahiro Numakawa,Toshika Okumiya,Noemi Fusaki

doi:10.1016/j.stemcr.2020.03.012

Ryutaro Kajihara, Takumi Era + Show 7 more

Open Access

https://doi.org/10.1016/j.stemcr.2020.03.012

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Abstract

SummaryGM1 gangliosidosis is a lysosomal storage disease caused by loss of lysosomal β-galactosidase activity and characterized by progressive neurodegeneration due to massive accumulation of GM1 ganglioside in the brain. Here, we generated induced pluripotent stem cells (iPSCs) derived from patients with GM1 gangliosidosis, and the resultant neurons showed impaired neurotransmitter release as a presynaptic function and accumulation of GM1 ganglioside. Treatment of normal neurons with GM1 ganglioside also disturbed presynaptic function. A high-content drug-screening system was then established and identified two compounds as drug candidates for GM1 gangliosidosis. Treatment of the patient-derived neurons with the candidate agents activated autophagy pathways, reducing GM1 ganglioside accumulation in vitro and in vivo, and restoring the presynaptic dysfunction. Our findings thus demonstrated the potential value of patient-derived iPSC lines as cellular models of GM1 gangliosidosis and revealed two potential therapeutic agents for future clinical application.

Highlights

GM1 gangliosidosis is a lysosomal storage disorder characterized by abnormal accumulation of GM1 ganglioside
We confirmed that the induced pluripotent stem cells (iPSCs) lines derived from patients A138 and A360 had a normal karyotype of 46XX, whereas those from patient A154 showed an abnormal karyotype of 46XX, add(9) (p24, arrow), and the abnormal karyotypes can affect the results in further experiments (Figure S1E)
GM2 and GM3 gangliosides were accumulated in the disease-derived neural stem cells (NSCs) (Figure 1C), and together, these results suggest that the NSCs derived from GM1-iPSCs mirror the biochemical phenotype of GM1 gangliosidosis

Summary

Introduction

GM1 gangliosidosis is a lysosomal storage disorder characterized by abnormal accumulation of GM1 ganglioside. The main clinical feature of the disease is neural dysfunction due to massive GM1 ganglioside deposition in the central nervous system (CNS) (Sandhoff and Harzer, 2013). This abnormal deposition is caused by a deficiency in lysosomal b-galactosidase (b-GAL) activity that limits the patients’ ability to degrade GM1 ganglioside in lysosomes and eventually leads to excessive GM1 ganglioside accumulation, in the brain. The infantile form develops by the age of 6 months and exhibits the most severe symptoms, such as developmental regression, seizures, eye abnormality, and hepatosplenomegaly. The adult form has milder symptoms such as dystonia and progresses chronically (Sandhoff and Harzer, 2013)

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Conclusion