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Patient iPSC-derived neural stem cells display progressive enlargement of lysosomes and disruptions of glycosaminoglycan pathway and autophagy in concordance with clinical severity of Mucopolysaccharidosis I

ABSTRACT: Patient iPSC-derived neural stem cells display progressive enlargement of lysosomes and disruptions of glycosaminoglycan pathway and autophagy in concordance with clinical severity of Mucopolysaccharidosis I

PROVIDER: PRJNA438517 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6844220_1.fastq.gz	Fastqsanger.gz
	SRR6844220_2.fastq.gz	Fastqsanger.gz
	SRR6844221_1.fastq.gz	Fastqsanger.gz
	SRR6844221_2.fastq.gz	Fastqsanger.gz
	SRR6844222_1.fastq.gz	Fastqsanger.gz

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Patient iPSC-derived neural stem cells display progressive enlargement of lysosomes and disruptions of glycosaminoglycan pathway and autophagy in concordance with clinical severity of Mucopolysaccharidosis I

Project description:Mucopolysaccharidosis type I (MPS I) is caused by genetic defects in alpha-L-iduronidase (IDUA), a lysosomal enzyme involved in the breakdown and recycling of glycosaminoglycans (GAGs). Although an enzyme replacement therapy is available, the efficacy for the treatment of neuropathic symptoms is limited. To facilitate drug discovery and model disease pathophysiology, we have generated neural stem cells (NSCs) from MPS I patient-derived iPSCs. NSCs exhibited characteristic disease phenotypes with deficiency of alpha-L-iduronidase (IDUA), accumulation of glycosaminoglycans (GAGs) and enlargement of lysosomes, correlating with the severity of clinical symptoms. Transcriptome profiling of NSCs revealed differential expression of 429 genes that changed more extensively in the more severe Hurler syndrome subgroup compared to the Hurler-Scheie (median severe) and Scheie (less severe) subgroups. Clustering and pathway analyses demonstrated high concordance of the severity of neurological defects with marked dysregulation of GAG biosynthesis and degradation, lysosomal function and extracellular matrix. Gene Ontology (GO) analysis identified a dramatic upregulation of autophagy pathway, especially in the Hurler syndrome. Thus, GAG accumulation in the patient cells disrupts lysosomal homeostasis affecting multiple related cellular pathways which compensates for IDUA deficiency. These dysregulated process likely lead to enhanced autophagy and more severe disease states. Our studies provide useful tools for clinical biomarker development and potential targets for drug development.

2018-10-18 | GSE111906 | GEO

A Drosophila model of mucopolysaccharidosis IIIB

Project description:Mucopolysaccharidosis IIIB (MPS IIIB) is a rare genetic disorder caused by defects in α-N-acetylglucosaminidase, which breaks down extracellular heparan sulfate. Symptoms progress from hyperactivity and sleep disruptions during childhood to severe neurodegeneration during adolescence. To generate an MPS IIIB model in the fruitfly, Drosophila melanogaster, we introduced mutations in the corresponding fly enzyme that correlate with patient mutations. The fly model recapitulates sleep fragmentation and hyperactivity observed in patients and enlarged lysosomes in the brain. Genes associated with synaptic function and neurodevelopment showed altered expression in the brain. The Drosophila model can enable future development of therapies for MPS IIIB.

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Transcription profiling of normal and Mucopolysaccharidosis type VI rat fibroblast-like synoviocytes

Project description:Gene expression in 9 month-old Mucopolysaccharidosis type VI rat fibroblast-like synoviocytes (FLS) were compared to age-matched normal rat FLS

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Zebrafish models of Mucopolysaccharidosis types IIIA, B, & C show hyperactivity and changes in oligodendrocyte state

Project description:Sanfilippo syndrome childhood dementia, also known as mucopolysaccharidosis type III (MPS III), is a rare inherited lysosomal storage disorder. Subtypes of MPS III are caused by deficiencies in one of four enzymes required for degradation of the glycosaminoglycan heparan sulfate (HS). An inability to degrade HS leads to progressive neurodegeneration and death in the second or third decades of life. Knowledge of MPS III pathogenesis is incomplete, and no effective therapies exist. We generated the hypomorphic mutations sgshS387Lfs, nagluA603Efs and hgsnatG577Sfsin the endogenous zebrafish genes orthologous to human SGSH, NAGLU, and HGSNAT that are loci for mutations causing MPS III subtypes MPS IIIA, B and C respectively. Our models display the primary MPS III disease signature of significant brain accumulation of HS, while behavioural analyses support hyperactivity phenotypes. Brain transcriptome analysis revealed changes related to lysosomal, glycosaminoglycan, immune system and iron homeostasis biology in all three models but also distinct differences in brain transcriptome state between models. The transcriptome analysis also indicated marked disturbance of the oligodendrocyte cell state in the brains of MPS IIIA, B and C zebrafish, supporting that effects on this cell type are an early and consistent characteristic of MPS III. Overall, our zebrafish models recapture key characteristics of the human disease and phenotypes seen in mouse models. Our models will allow exploitation of the zebrafish’s extreme fecundity and accessible anatomy to dissect the pathological mechanisms both common and divergent between the MPS IIIA, B, and C subtypes.

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Project description:A Drosophila model of mucopolysaccharidosis IIIB

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Project description:Emerging evidences suggest that both function and position of organelles are pivotal for tumor cell dissemination. Among them, lysosomes stand out as they integrate metabolic sensing with gene regulation and secretion of proteases. Yet, how lysosomes function is linked to their position and thereby control metastatic progression remains elusive. Here, we analyzed lysosome subcellular distribution in micropatterned patient-derived melanoma cells and found that lysosome spreading scales with their aggressiveness. Peripheral lysosomes promote invadopodia-based matrix degradation and invasion of melanoma cells which is directly linked to their lysosomal and cell transcriptional programs. When controlling lysosomal positioning using chemo-genetical heterodimerization in melanoma cells, we demonstrated that perinuclear clustering impairs lysosomal secretion, matrix degradation and invasion. Impairing lysosomal spreading in a zebrafish metastasis model significantly reduces invasive outgrowth. Our study provides a mechanistic demonstration that lysosomal positioning controls cell invasion, illustrating the importance of organelle adaptation in carcinogenesis.

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Project description:Lysosomal Storage Disorders (LSDs) are a group of about 50 metabolic disorders, sharing the inability to degrade specific endolysosomal substrates. This results in failure of cellular functions in many organ systems including brain in most patients, which show a progressive neurodegeneration. In this study we performed an RNA-Seq analysis of two brain areas (cerebral cortex and midbrain/diencephalon/hippocampus) of the mouse model for Mucopolysaccharidosis type II, a neurodegenerative LSD.

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Peripheral positioning of lysosomes supports melanoma aggressiveness

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Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation

Project description:Lysosomes are central platforms for not only the degradation of macromolecules but also the integration of multiple signaling pathways. However, whether and how lysosomes mediate the mitochondrial stress response (MSR) remain largely unknown. Here, we demonstrate that lysosomal acidification via the vacuolar H+-ATPase (v-ATPase) is essential for the transcriptional activation of the mitochondrial unfolded protein response (UPRmt). Mitochondrial stress stimulates v-ATPase-mediated lysosomal activation of the mechanistic target of rapamycin complex 1 (mTORC1), which then directly phosphorylates the MSR transcription factor, activating transcription factor 4 (ATF4). Disruption of mTORC1-dependent ATF4 phosphorylation blocks the UPRmt, but not other similar stress responses, such as the UPRER. Finally, ATF4 phosphorylation downstream of the v-ATPase/mTORC1 signaling is indispensable for sustaining mitochondrial redox homeostasis and protecting cells from reactive oxygen species (ROS)-associated cell death upon mitochondrial stress. Thus, v-ATPase/mTORC1-mediated ATF4 phosphorylation via lysosomes links mitochondrial stress to UPRmt activation and mitochondrial function resilience.

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Molecular Profiling of Failed Endochondral Ossification in Mucopolysaccharidosis VII

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