Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation

Allende, María L.; Cook, Emily K.; Larman, Bridget C.; Nugent, Adrienne; Brady, Jacqueline M.; Golebiowski, Diane; Sena‐Esteves, Miguel; Tifft, Cynthia J.; Proia, Richard L.

doi:10.1194/jlr.m081323

Cited by 86 publications

(68 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Analysis of hexb −/− mouse fetal neuronal stem cells (NSCs), also called radial glia, revealed a more frequent differentiation towards the astrocyte lineage rather than neurons, indicating abnormal differentiation of brain cells (Ogawa et al, ). SD patient IPS cell‐derived organoids also showed aberrant neuronal differentiation (Allende et al, ). These studies suggest that HEXB deficiency could intrinsically affect neuronal differentiation and induce increased astrocyte numbers, which could be an initiating event in the pathogenesis of SD.…”

Section: Introductionmentioning

confidence: 99%

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

Kuil

Martí

Mascaro

et al. 2019

Glia

View full text Add to dashboard Cite

Sphingolipidoses are severe, mostly infantile lysosomal storage disorders (LSDs) caused by defective glycosphingolipid degradation. Two of these sphingolipidoses, Tay Sachs and Sandhoff diseases, are caused by β‐Hexosaminidase (HEXB) enzyme deficiency, resulting in ganglioside (GM2) accumulation and neuronal loss. The precise sequence of cellular events preceding, and leading to, neuropathology remains unclear, but likely involves inflammation and lysosomal accumulation of GM2 in multiple cell types. We aimed to determine the consequences of Hexb activity loss for different brain cell types using zebrafish. Hexb deficient zebrafish (hexb−/−) showed lysosomal abnormalities already early in development both in radial glia, which are the neuronal and glial progenitors, and in microglia. Additionally, at 5 days postfertilization, hexb−/− zebrafish showed reduced locomotor activity. Although specific oligosaccharides accumulate in the adult brain, hexb−/−) zebrafish are viable and apparently resistant to Hexb deficiency. In all, we identified cellular consequences of loss of Hexb enzyme activity during embryonic brain development, showing early effects on glia, which possibly underlie the behavioral aberrations. Hereby, we identified clues into the contribution of non‐neuronal lysosomal abnormalities in LSDs affecting the brain and provide a tool to further study what underlies the relative resistance to Hexb deficiency in vivo.

show abstract

Section: Introductionmentioning

confidence: 99%

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

Kuil

Martí

Mascaro

et al. 2019

Glia

View full text Add to dashboard Cite

show abstract

“…Human iPSCs have been differentiated into neurons and/or glial cells to model the neural defects associated to several lysosomal storage diseases (LSDs) including mucopolysaccharidosis (Bayó-Puxan et al, 2018;Canals et al, 2015;Kobolák et al, 2019;Lemonnier et al, 2011;Vallejo-Diez et al, 2018), Niemann−Pick type C (Maetzel et al, 2014;Ordoñez and Steele, 2016;Trilck et al, 2013;Yu et al, 2014), Pompe disease (Higuchi et al, 2014), Gaucher disease (Panicker et al, 2012;Sun et al, 2015;Tiscornia et al, 2013), GM1 and GM2 gangliosidosis (Son et al, 2015) (Allende et al, 2018), NCL (Lojewski et al, 2014), and MLD (Frati et al, 2018;Meneghini et al, 2017). To our knowledge this is the first report describing a human iPSC-based neural model of GLD.…”

Section: Discussionmentioning

confidence: 99%

Human iPSC-based neurodevelopmental models of globoid cell leukodystrophy uncover patient- and cell type-specific disease phenotypes

Mangiameli

Cecchele

Morena

et al. 2020

Preprint

View full text Add to dashboard Cite

21Globoid Cell Leukodystrophy (GLD, or Krabbe disease) is a rare lysosomal storage disease caused 22 by inherited deficiency of β-galactocerebrosidase (GALC). The build-up of psychosine and other 23 undegraded galactosylsphingolipids in the nervous system causes serious demyelination and 24 neurodegeneration. The molecular mechanisms of GLD are poorly elucidated in neural cells and whether 25 murine systems faithfully recapitulate critical aspects of the human disease is still to be defined. 26Here, we established a collection of GLD patient-specific induced pluripotent stem cell (iPSC) 27 lines. We differentiated iPSCs from two patients -bearing different disease-causing mutations -into 28 neural progenitors cells (NPCs) and their neuronal/glial progeny, assessing the impact of GALC deficiency 29 and lentiviral vector-mediated GALC rescue/overexpression by means of phenotypic, biochemical, 30 molecular, and lipidomic analysis. We show a progressive increase of psychosine during the 31 differentiation of GLD NPCs to neurons and glia. We report an early and persistent impairment of glial 32 and neuronal differentiation in GLD cultures, with peculiar differences observed in the two GLD lines. 33GLD cells display a global unbalance of lipid composition during the iPSC to neural differentiation and 34 early activation of cellular senescence, depending on the disease-causing mutation. Restoration of GALC 35 activity normalizes the primary pathological hallmarks and partially rescues the differentiation program 36 of GLD NPCs. 37Our results show that multiple mechanisms besides psychosine toxicity concur to CNS pathology 38 in GLD and highlight the need of a timely regulated GALC expression for proper lineage commitment and 39 differentiation of human NPCs. These findings have important implications for establishing tailored 40 cell/gene therapy strategies to enhance disease correction in GLD. 41 42

show abstract

“…The use of a cerebral SD organoid model, generated from patient-derived iPS cells, has been an interesting approximation to the discovery of novel implications of GM2 accumulation [ 67 ]. In this context, recent findings have described that impaired Hex activity promotes an increase in the size of the cerebral organoids, which was corrected after transduction of HEXA and HEXB cDNAs by using adeno-associated virus (AAV) vectors [ 68 ]. In agreement with these results, and using HEXB deficient zebrafish embryos, Kuil et al, 2019 found an increase in the lysosomal speckles in radial glia [ 69 ], which are progenitor cells able to difference in neurons, astrocytes, and oligodendrocytes [ 70 ].…”

Section: Physiopathology Of Gm2 Gangliosidosesmentioning

confidence: 99%

GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies

Leal

Benincore-Flórez

Solano-Galarza

et al. 2020

IJMS

View full text Add to dashboard Cite

GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay–Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood–brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g., intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.

show abstract

Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation

Cited by 86 publications

References 69 publications

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

Human iPSC-based neurodevelopmental models of globoid cell leukodystrophy uncover patient- and cell type-specific disease phenotypes

GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies

Contact Info

Product

Resources

About