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Volume 22
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Review

Myelin Defects in Niemann–Pick Type C Disease: Mechanisms and Possible Therapeutic Perspectives

by
Antonietta Bernardo
1,†,
Chiara De Nuccio
2,†,
Sergio Visentin
1,
Alberto Martire
1,
Luisa Minghetti
2,
Patrizia Popoli
1 and
Antonella Ferrante
1,*
1
National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
2
Research Coordination and Support Service, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally.
Int. J. Mol. Sci. 2021, 22(16), 8858; https://doi.org/10.3390/ijms22168858
Submission received: 20 July 2021 / Revised: 11 August 2021 / Accepted: 16 August 2021 / Published: 17 August 2021
(This article belongs to the Special Issue Multiple Sclerosis and Demyelinating Pathologies: Mechanisms and Cutting-Edge Therapies)
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Abstract

Niemann–Pick type C (NPC) disease is a wide-spectrum clinical condition classified as a neurovisceral disorder affecting mainly the liver and the brain. It is caused by mutations in one of two genes, NPC1 and NPC2, coding for proteins located in the lysosomes. NPC proteins are deputed to transport cholesterol within lysosomes or between late endosome/lysosome systems and other cellular compartments, such as the endoplasmic reticulum and plasma membrane. The first trait of NPC is the accumulation of unesterified cholesterol and other lipids, like sphingosine and glycosphingolipids, in the late endosomal and lysosomal compartments, which causes the blockade of autophagic flux and the impairment of mitochondrial functions. In the brain, the main consequences of NPC are cerebellar neurodegeneration, neuroinflammation, and myelin defects. This review will focus on myelin defects and the pivotal importance of cholesterol for myelination and will offer an overview of the molecular targets and the pharmacological strategies so far proposed, or an object of clinical trials for NPC. Finally, it will summarize recent data on a new and promising pharmacological perspective involving A2A adenosine receptor stimulation in genetic and pharmacological NPC dysmyelination models.
Keywords: Niemann–Pick type C disease; myelination; oligodendrocytes; cholesterol; mitochondrial impairment; A2AR; adenosine Niemann–Pick type C disease; myelination; oligodendrocytes; cholesterol; mitochondrial impairment; A2AR; adenosine

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MDPI and ACS Style

Bernardo, A.; De Nuccio, C.; Visentin, S.; Martire, A.; Minghetti, L.; Popoli, P.; Ferrante, A. Myelin Defects in Niemann–Pick Type C Disease: Mechanisms and Possible Therapeutic Perspectives. Int. J. Mol. Sci. 2021, 22, 8858. https://doi.org/10.3390/ijms22168858

AMA Style

Bernardo A, De Nuccio C, Visentin S, Martire A, Minghetti L, Popoli P, Ferrante A. Myelin Defects in Niemann–Pick Type C Disease: Mechanisms and Possible Therapeutic Perspectives. International Journal of Molecular Sciences. 2021; 22(16):8858. https://doi.org/10.3390/ijms22168858

Chicago/Turabian Style

Bernardo, Antonietta, Chiara De Nuccio, Sergio Visentin, Alberto Martire, Luisa Minghetti, Patrizia Popoli, and Antonella Ferrante. 2021. "Myelin Defects in Niemann–Pick Type C Disease: Mechanisms and Possible Therapeutic Perspectives" International Journal of Molecular Sciences 22, no. 16: 8858. https://doi.org/10.3390/ijms22168858

APA Style

Bernardo, A., De Nuccio, C., Visentin, S., Martire, A., Minghetti, L., Popoli, P., & Ferrante, A. (2021). Myelin Defects in Niemann–Pick Type C Disease: Mechanisms and Possible Therapeutic Perspectives. International Journal of Molecular Sciences, 22(16), 8858. https://doi.org/10.3390/ijms22168858

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