Modeling neuronopathic storage diseases with patient-derived culture systems

Friederike Zunke, Joe Mazzulli

Research output: Contribution to journalReview article

Abstract

Lysosomes are organelles involved in the degradation and recycling of macromolecules, and play a critical role in sensing metabolic information in the cell. A class of rare metabolic diseases called lysosomal storage disorders (LSD) are characterized by lysosomal dysfunction and the accumulation of macromolecular substrates. The central nervous system appears to be particularly vulnerable to lysosomal dysfunction, since many LSDs are characterized by severe, widespread neurodegeneration with pediatric onset. Furthermore, variants in lysosomal genes are strongly associated with some common neurodegenerative disorders such as Parkinson's disease (PD). To better understand disease pathology and develop novel treatment strategies, it is critical to study the fundamental molecular disease mechanisms in the affected cell types that harbor endogenously expressed mutations. The discovery of methods for reprogramming of patient-derived somatic cells into induced pluripotent stem cells (iPSCs), and their differentiation into distinct neuronal and glial cell types, have provided novel opportunities to study mechanisms of lysosomal dysfunction within the relevant, vulnerable cell types. These models also expand our ability to develop and test novel therapeutic targets. We discuss recently developed methods for iPSC differentiation into distinct neuronal and glial cell types, while addressing the need for meticulous experimental techniques and parameters that are essential to accurately identify inherent cellular pathologies. iPSC models for neuronopathic LSDs and their relationship to sporadic age-related neurodegeneration are also discussed. These models should facilitate the discovery and development of personalized therapies in the future.

Original languageEnglish (US)
Pages (from-to)147-162
Number of pages16
JournalNeurobiology of Disease
Volume127
DOIs
StatePublished - Jul 1 2019

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Induced Pluripotent Stem Cells
Lysergic Acid Diethylamide
Neuroglia
Cell Differentiation
Pathology
Metabolic Diseases
Recycling
Rare Diseases
Lysosomes
Neurodegenerative Diseases
Organelles
Parkinson Disease
Therapeutics
Central Nervous System
Pediatrics
Mutation
Genes

ASJC Scopus subject areas

  • Neurology

Cite this

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title = "Modeling neuronopathic storage diseases with patient-derived culture systems",
abstract = "Lysosomes are organelles involved in the degradation and recycling of macromolecules, and play a critical role in sensing metabolic information in the cell. A class of rare metabolic diseases called lysosomal storage disorders (LSD) are characterized by lysosomal dysfunction and the accumulation of macromolecular substrates. The central nervous system appears to be particularly vulnerable to lysosomal dysfunction, since many LSDs are characterized by severe, widespread neurodegeneration with pediatric onset. Furthermore, variants in lysosomal genes are strongly associated with some common neurodegenerative disorders such as Parkinson's disease (PD). To better understand disease pathology and develop novel treatment strategies, it is critical to study the fundamental molecular disease mechanisms in the affected cell types that harbor endogenously expressed mutations. The discovery of methods for reprogramming of patient-derived somatic cells into induced pluripotent stem cells (iPSCs), and their differentiation into distinct neuronal and glial cell types, have provided novel opportunities to study mechanisms of lysosomal dysfunction within the relevant, vulnerable cell types. These models also expand our ability to develop and test novel therapeutic targets. We discuss recently developed methods for iPSC differentiation into distinct neuronal and glial cell types, while addressing the need for meticulous experimental techniques and parameters that are essential to accurately identify inherent cellular pathologies. iPSC models for neuronopathic LSDs and their relationship to sporadic age-related neurodegeneration are also discussed. These models should facilitate the discovery and development of personalized therapies in the future.",
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Modeling neuronopathic storage diseases with patient-derived culture systems. / Zunke, Friederike; Mazzulli, Joe.

In: Neurobiology of Disease, Vol. 127, 01.07.2019, p. 147-162.

Research output: Contribution to journalReview article

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