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Article ; Online: Demyelination and Na

Lee, Jeong Han / Park, Seojin / Perez-Flores, Maria C / Chen, Yingying / Kang, Mincheol / Choi, Jinsil / Levine, Lauren / Gratton, Michael Anne / Zhao, Jie / Notterpek, Lucia / Yamoah, Ebenezer N

eNeuro

2024 Volume 11, Issue 2

Abstract: Altered expression of peripheral myelin protein 22 (PMP22) results in demyelinating peripheral neuropathy. PMP22 exhibits a highly restricted tissue distribution with marked expression in the myelinating Schwann cells of peripheral nerves. Auditory and ... ...

Abstract	Altered expression of peripheral myelin protein 22 (PMP22) results in demyelinating peripheral neuropathy. PMP22 exhibits a highly restricted tissue distribution with marked expression in the myelinating Schwann cells of peripheral nerves. Auditory and vestibular Schwann cells and the afferent neurons also express PMP22, suggesting a unique role in hearing and balancing. Indeed, neuropathic patients diagnosed with PMP22-linked hereditary neuropathies often present with auditory and balance deficits, an understudied clinical complication. To investigate the mechanism by which abnormal expression of PMP22 may cause auditory and vestibular deficits, we studied gene-targeted
MeSH term(s)	Animals ; Humans ; Mice ; Demyelinating Diseases/metabolism ; Mice, Knockout ; Myelin Proteins/genetics ; Myelin Proteins/metabolism ; Myelin Sheath/metabolism ; Schwann Cells/metabolism
Chemical Substances	Myelin Proteins ; PMP22 protein, human ; Pmp22 protein, mouse
Language	English
Publishing date	2024-02-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2800598-3
ISSN	2373-2822 ; 2373-2822
ISSN (online)	2373-2822
ISSN	2373-2822
DOI	10.1523/ENEURO.0462-23.2023
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Article ; Online: Promoting peripheral myelin repair.

Zhou, Ye / Notterpek, Lucia

Experimental neurology

2016 Volume 283, Issue Pt B, Page(s) 573–580

Abstract: Compared to the central nervous system (CNS), peripheral nerves have a remarkable ability to regenerate and remyelinate. This regenerative capacity to a large extent is dependent on and supported by Schwann cells, the myelin-forming glial cells of the ... ...

Abstract	Compared to the central nervous system (CNS), peripheral nerves have a remarkable ability to regenerate and remyelinate. This regenerative capacity to a large extent is dependent on and supported by Schwann cells, the myelin-forming glial cells of the peripheral nervous system (PNS). In a variety of paradigms, Schwann cells are critical in the removal of the degenerated tissue, which is followed by remyelination of newly-regenerated axons. This unique plasticity of Schwann cells has been the target of myelin repair strategies in acute injuries and chronic diseases, such as hereditary demyelinating neuropathies. In one approach, the endogenous regenerative capacity of Schwann cells is enhanced through interventions such as exercise, electrical stimulation or pharmacological means. Alternatively, Schwann cells derived from healthy nerves, or engineered from different tissue sources have been transplanted into the PNS to support remyelination. These transplant approaches can then be further enhanced by exercise and/or electrical stimulation, as well as by the inclusion of biomaterial engineered to support glial cell viability and neurite extension. Advances in our basic understanding of peripheral nerve biology, as well as biomaterial engineering, will further improve the functional repair of myelinated peripheral nerves.
MeSH term(s)	Animals ; Demyelinating Diseases/pathology ; Demyelinating Diseases/physiopathology ; Humans ; Myelin Sheath/physiology ; Nerve Regeneration/physiology ; Neuroglia/physiology ; Peripheral Nerves/pathology
Language	English
Publishing date	2016-09
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	207148-4
ISSN	1090-2430 ; 0014-4886
ISSN (online)	1090-2430
ISSN	0014-4886
DOI	10.1016/j.expneurol.2016.04.007
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Zs.A 184: Show issues

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Article: Neurotrophins in myelination: a new role for a puzzling receptor.

Notterpek, Lucia

Trends in neurosciences

2003 Volume 26, Issue 5, Page(s) 232–234

Abstract: Binding of neurotrophins to p75(NTR) was recently identified as a positive signal for myelination by Schwann cells. This new finding adds yet another distinct biological role to the growing list of functions of p75(NTR) in the nervous system and ... ...

Abstract	Binding of neurotrophins to p75(NTR) was recently identified as a positive signal for myelination by Schwann cells. This new finding adds yet another distinct biological role to the growing list of functions of p75(NTR) in the nervous system and identifies a novel target for promoting remyelination in peripheral neuropathies or post-nerve-injury.
MeSH term(s)	Animals ; Brain-Derived Neurotrophic Factor/metabolism ; Cells, Cultured ; Demyelinating Diseases/metabolism ; Demyelinating Diseases/physiopathology ; Forecasting ; Humans ; Nerve Growth Factors/classification ; Nerve Growth Factors/metabolism ; Peripheral Nervous System Diseases/metabolism ; Peripheral Nervous System Diseases/physiopathology ; Receptor, Nerve Growth Factor ; Receptors, Nerve Growth Factor/metabolism ; Schwann Cells/metabolism
Chemical Substances	Brain-Derived Neurotrophic Factor ; Nerve Growth Factors ; Receptor, Nerve Growth Factor ; Receptors, Nerve Growth Factor
Language	English
Publishing date	2003-05
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	282488-7
ISSN	1878-108X ; 0166-2236 ; 0378-5912
ISSN (online)	1878-108X
ISSN	0166-2236 ; 0378-5912
DOI	10.1016/S0166-2236(03)00099-7
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Zs.A 1442: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 53: Show issues

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Article ; Online: Dietary restriction supports peripheral nerve health by enhancing endogenous protein quality control mechanisms.

Lee, Sooyeon / Notterpek, Lucia

Experimental gerontology

2012 Volume 48, Issue 10, Page(s) 1085–1090

Abstract: The peripheral nervous system (PNS) comprises of an extensive network of connections that convey information between the central nervous system (CNS) and peripheral organs. Long myelinated nerve fibers are particularly susceptible to age-related changes, ...

Abstract	The peripheral nervous system (PNS) comprises of an extensive network of connections that convey information between the central nervous system (CNS) and peripheral organs. Long myelinated nerve fibers are particularly susceptible to age-related changes, as maintenance of the insulating glial membrane requires extensive synthesis and processing of many proteins. In rodent models, peripheral demyelination caused by genetic risk factors or by normal aging are attenuated by intermittent fasting (IF) or calorie restriction (CR) supporting a role for dietary intervention in preserving neural function. This review will summarize recent studies examining mechanisms by which life-long CR or extended IF supports peripheral nerve health.
MeSH term(s)	Aging/physiology ; Caloric Restriction ; Fasting/physiology ; Homeostasis/physiology ; Humans ; Myelin Sheath/physiology ; Nerve Degeneration/physiopathology ; Nerve Tissue Proteins/physiology ; Peripheral Nervous System/physiology
Chemical Substances	Nerve Tissue Proteins
Language	English
Publishing date	2012-12-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	390992-x
ISSN	1873-6815 ; 0531-5565
ISSN (online)	1873-6815
ISSN	0531-5565
DOI	10.1016/j.exger.2012.12.008
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Zs.A 579: Show issues

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Article ; Online: Kir4.1 is specifically expressed and active in non-myelinating Schwann cells.

Procacci, Nicole M / Hastings, Robert Louis / Aziz, Aamir A / Christiansen, Nina M / Zhao, Jie / DeAngeli, Claire / LeBlanc, Normand / Notterpek, Lucia / Valdez, Gregorio / Gould, Thomas W

Glia

2022 Volume 71, Issue 4, Page(s) 926–944

Abstract: Non-myelinating Schwann cells (NMSC) play important roles in peripheral nervous system formation and function. However, the molecular identity of these cells remains poorly defined. We provide evidence that Kir4.1, an inward-rectifying K+ channel encoded ...

Abstract	Non-myelinating Schwann cells (NMSC) play important roles in peripheral nervous system formation and function. However, the molecular identity of these cells remains poorly defined. We provide evidence that Kir4.1, an inward-rectifying K+ channel encoded by the KCNJ10 gene, is specifically expressed and active in NMSC. Immunostaining revealed that Kir4.1 is present in terminal/perisynaptic SCs (TPSC), synaptic glia at neuromuscular junctions (NMJ), but not in myelinating SCs (MSC) of adult mice. To further examine the expression pattern of Kir4.1, we generated BAC transgenic Kir4.1-CreER
MeSH term(s)	Mice ; Animals ; Schwann Cells/metabolism ; Myelin Sheath/metabolism ; Mice, Transgenic ; Sciatic Nerve/metabolism ; Tamoxifen/pharmacology
Chemical Substances	Tamoxifen (094ZI81Y45)
Language	English
Publishing date	2022-12-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639414-0
ISSN	1098-1136 ; 0894-1491
ISSN (online)	1098-1136
ISSN	0894-1491
DOI	10.1002/glia.24315
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Zs.A 2345: Show issues

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Article ; Online: MicroRNAs in oligodendrocyte and Schwann cell differentiation.

Dugas, Jason C / Notterpek, Lucia

Developmental neuroscience

2011 Volume 33, Issue 1, Page(s) 14–20

Abstract: MicroRNAs (miRNAs) are a class of small (approx. 22 nt) noncoding RNAs that are capable of post-transcriptionally silencing mRNAs that contain sequences complementary to the miRNAs' 7- to 8-bp 'seed' sequence. As single miRNAs are often predicted to ... ...

Abstract	MicroRNAs (miRNAs) are a class of small (approx. 22 nt) noncoding RNAs that are capable of post-transcriptionally silencing mRNAs that contain sequences complementary to the miRNAs' 7- to 8-bp 'seed' sequence. As single miRNAs are often predicted to target up to hundreds of individual transcripts, miRNAs are able to broadly affect the overall protein expression state of the cell. This can translate into global effects on cellular health and differentiation state. Recently, several reports have identified crucial roles for miRNAs in controlling the production, differentiation, and health of myelinating cells of the mammalian nervous system. In this review, we will discuss how individual miRNAs regulate these various processes, and also how miRNA production in general is required for several stages of myelin generation and maintenance.
MeSH term(s)	Brain Neoplasms/genetics ; Cell Differentiation/genetics ; Cell Differentiation/physiology ; DEAD-box RNA Helicases/metabolism ; Gene Expression ; Guillain-Barre Syndrome/genetics ; Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Myelin Sheath/metabolism ; Oligodendroglia/physiology ; Ribonuclease III/metabolism ; Schwann Cells/physiology
Chemical Substances	MicroRNAs ; Ribonuclease III (EC 3.1.26.3) ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2011-02-23
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	556887-0
ISSN	1421-9859 ; 0378-5866
ISSN (online)	1421-9859
ISSN	0378-5866
DOI	10.1159/000323919
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Zs.A 1438: Show issues

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Article ; Online: Autophagy aids membrane expansion by neuropathic Schwann cells.

Rangaraju, Sunitha / Notterpek, Lucia

Autophagy

2011 Volume 7, Issue 2, Page(s) 238–239

Abstract: Demyelinating peripheral neuropathies associated with abnormal expression of peripheral myelin protein 22 (PMP22) involve the formation of cytosolic protein aggregates within Schwann cells. Towards developing a therapy for these progressive ... ...

Abstract	Demyelinating peripheral neuropathies associated with abnormal expression of peripheral myelin protein 22 (PMP22) involve the formation of cytosolic protein aggregates within Schwann cells. Towards developing a therapy for these progressive neurodegenerative diseases, we assessed whether pharmacological activation of autophagy by rapamycin (RM) could prevent protein aggregation and enhance Schwann cell myelination. Indeed, we found that glial cells from neuropathic mice activate autophagy in response to RM and produce abundant myelin internodes. Lentivirus-mediated shRNA shutdown of Atg12 abrogates the improvements in myelin production, demonstrating that autophagy is critical for the observed benefits.
MeSH term(s)	Animals ; Autophagy/drug effects ; Cell Membrane/drug effects ; Cell Membrane/metabolism ; Ganglia, Spinal/drug effects ; Ganglia, Spinal/metabolism ; Mice ; Myelin Proteins/metabolism ; Peripheral Nerves/drug effects ; Peripheral Nerves/metabolism ; Peripheral Nerves/pathology ; Peripheral Nervous System Diseases/metabolism ; Peripheral Nervous System Diseases/pathology ; Schwann Cells/drug effects ; Schwann Cells/metabolism ; Schwann Cells/pathology ; Sirolimus/pharmacology
Chemical Substances	Myelin Proteins ; Pmp22 protein, mouse ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2011-02-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.7.2.14278
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Zs.A 6741: Show issues

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Article ; Online: Subcellular diversion of cholesterol by gain- and loss-of-function mutations in PMP22.

Zhou, Ye / Borchelt, David / Bauson, Jodi C / Fazio, Sergio / Miles, Joshua R / Tavori, Hagai / Notterpek, Lucia

Glia

2020 Volume 68, Issue 11, Page(s) 2300–2315

Abstract: Abnormalities of the peripheral myelin protein 22 (PMP22) gene, including duplication, deletion and point mutations are a major culprit in Type 1 Charcot-Marie-Tooth (CMT) diseases. The complete absence of PMP22 alters cholesterol metabolism in Schwann ... ...

Abstract	Abnormalities of the peripheral myelin protein 22 (PMP22) gene, including duplication, deletion and point mutations are a major culprit in Type 1 Charcot-Marie-Tooth (CMT) diseases. The complete absence of PMP22 alters cholesterol metabolism in Schwann cells, which likely contributes to myelination deficits. Here, we examined the subcellular trafficking of cholesterol in distinct models of PMP22-linked neuropathies. In Schwann cells from homozygous Trembler J (TrJ) mice carrying a Leu16Pro mutation, cholesterol was retained with TrJ-PMP22 in the Golgi, alongside a corresponding reduction in its plasma membrane level. PMP22 overexpression, which models CMT1A caused by gene duplication, triggered cholesterol sequestration to lysosomes, and reduced ATP-binding cassette transporter-dependent cholesterol efflux. Conversely, lysosomal targeting of cholesterol by U18666A treatment increased wild type (WT)-PMP22 levels in lysosomes. Mutagenesis of a cholesterol recognition motif, or CRAC domain, in human PMP22 lead to increased levels of PMP22 in the ER and Golgi compartments, along with higher cytosolic, and lower membrane-associated cholesterol. Importantly, cholesterol trafficking defects observed in PMP22-deficient Schwann cells were rescued by WT but not CRAC-mutant-PMP22. We also observed that myelination deficits in dorsal root ganglia explants from heterozygous PMP22-deficient mice were improved by cholesterol supplementation. Collectively, these findings indicate that PMP22 is critical in cholesterol metabolism, and this mechanism is likely a contributing factor in PMP22-linked hereditary neuropathies. Our results provide a basis for understanding how altered expression of PMP22 impacts cholesterol metabolism.
MeSH term(s)	Animals ; Charcot-Marie-Tooth Disease/genetics ; Cholesterol ; Mice ; Mutation/genetics ; Myelin Proteins ; Schwann Cells
Chemical Substances	Myelin Proteins ; Pmp22 protein, mouse ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2020-06-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639414-0
ISSN	1098-1136 ; 0894-1491
ISSN (online)	1098-1136
ISSN	0894-1491
DOI	10.1002/glia.23840
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Zs.A 2345: Show issues

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Article ; Online: Inducible HSP70 is critical in preventing the aggregation and enhancing the processing of PMP22.

Chittoor-Vinod, Vinita G / Lee, Sooyeon / Judge, Sarah M / Notterpek, Lucia

ASN neuro

2015 Volume 7, Issue 1

Abstract: Chaperones, also called heat shock proteins (HSPs), transiently interact with proteins to aid their folding, trafficking, and degradation, thereby directly influencing the transport of newly synthesized molecules. Induction of chaperones provides a ... ...

Abstract	Chaperones, also called heat shock proteins (HSPs), transiently interact with proteins to aid their folding, trafficking, and degradation, thereby directly influencing the transport of newly synthesized molecules. Induction of chaperones provides a potential therapeutic approach for protein misfolding disorders, such as peripheral myelin protein 22 (PMP22)-associated peripheral neuropathies. Cytosolic aggregates of PMP22, linked with a demyelinating Schwann cell phenotype, result in suppression of proteasome activity and activation of proteostatic mechanisms, including the heat shock pathway. Although the beneficial effects of chaperones in preventing the aggregation and improving the trafficking of PMP22 have been repeatedly observed, the requirement for HSP70 in events remains elusive. In this study, we show that activation of the chaperone pathway in fibroblasts from PMP22 duplication-associated Charcot-Marie-Tooth disease type 1A patient with an FDA-approved small molecule increases HSP70 expression and attenuates proteasome dysfunction. Using cells from an HSP70.1/3(-/-) (inducible HSP70) mouse model, we demonstrate that under proteotoxic stress, this chaperone is critical in preventing the aggregation of PMP22, and this effect is aided by macroautophagy. When examined at steady-state, HSP70 appears to play a minor role in the trafficking of wild-type-PMP22, while it is crucial for preventing the buildup of the aggregation-prone Trembler-J-PMP22. HSP70 aids the processing of Trembler-J-PMP22 through the Golgi and its delivery to lysosomes via Rab7-positive vesicles. Together, these results demonstrate a key role for inducible HSP70 in aiding the processing and hindering the accumulation of misfolded PMP22, which in turn alleviates proteotoxicity within the cells.
MeSH term(s)	Acetylcysteine/analogs & derivatives ; Acetylcysteine/pharmacology ; Adenine/analogs & derivatives ; Adenine/pharmacology ; Animals ; Autophagy/drug effects ; Autophagy/genetics ; Cells, Cultured ; Charcot-Marie-Tooth Disease/pathology ; Cysteine Proteinase Inhibitors/pharmacology ; Embryo, Mammalian ; Fibroblasts/drug effects ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/genetics ; Gene Expression Regulation/physiology ; HSP70 Heat-Shock Proteins/genetics ; HSP70 Heat-Shock Proteins/metabolism ; Humans ; Mice ; Mice, Transgenic ; Middle Aged ; Myelin Proteins/metabolism ; Proteasome Endopeptidase Complex/genetics ; Proteasome Endopeptidase Complex/metabolism ; Protein Aggregation, Pathological/metabolism ; Protein Aggregation, Pathological/prevention & control ; Protein Transport/drug effects ; Protein Transport/genetics ; Pyridines/pharmacology ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Skin/pathology ; Ubiquitin/genetics ; Ubiquitin/metabolism
Chemical Substances	6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-ylamine ; Cysteine Proteinase Inhibitors ; HSP70 Heat-Shock Proteins ; Myelin Proteins ; PMP22 protein, human ; Pyridines ; Ubiquitin ; lactacystin (133343-34-7) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Adenine (JAC85A2161) ; Acetylcysteine (WYQ7N0BPYC)
Language	English
Publishing date	2015-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2485467-0
ISSN	1759-0914 ; 1759-0914
ISSN (online)	1759-0914
ISSN	1759-0914
DOI	10.1177/1759091415569909
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Article ; Online: HSP90 Inhibitor, NVP-AUY922, Improves Myelination in Vitro and Supports the Maintenance of Myelinated Axons in Neuropathic Mice.

Chittoor-Vinod, Vinita G / Bazick, Hannah / Todd, Adrian G / Falk, Darin / Morelli, Kathryn H / Burgess, Robert W / Foster, Thomas C / Notterpek, Lucia

ACS chemical neuroscience

2019 Volume 10, Issue 6, Page(s) 2890–2902

Abstract: Hereditary demyelinating neuropathies linked to peripheral myelin protein 22 (PMP22) involve the disruption of normal protein trafficking and are therefore relevant targets for chaperone therapy. Using a small molecule HSP90 inhibitor, EC137, in cell ... ...

Abstract	Hereditary demyelinating neuropathies linked to peripheral myelin protein 22 (PMP22) involve the disruption of normal protein trafficking and are therefore relevant targets for chaperone therapy. Using a small molecule HSP90 inhibitor, EC137, in cell culture models, we previously validated the chaperone pathway as a viable target for therapy development. Here, we tested five commercially available inhibitors of HSP90 and identified BIIB021 and AUY922 to support Schwann cell viability and enhance chaperone expression. AUY922 showed higher efficacy, compared to BIIB021, in enhancing myelin synthesis in dorsal root ganglion explant cultures from neuropathic mice. For in vivo testing, we randomly assigned 2-3 month old C22 and 6 week old Trembler J (TrJ) mice to receive two weekly injections of either vehicle or AUY922 (2 mg/kg). By the intraperitoneal (i.p.) route, the drug was well-tolerated by all mice over the 5 month long study, without influence on body weight or general grooming behavior. AUY922 improved the maintenance of myelinated nerves of both neuropathic models and attenuated the decline in rotarod performance and peak muscle force production in C22 mice. These studies highlight the significance of proteostasis in neuromuscular function and further validate the HSP90 pathway as a therapeutic target for hereditary neuropathies.
MeSH term(s)	Animals ; Axons/drug effects ; Axons/pathology ; Charcot-Marie-Tooth Disease/pathology ; HSP90 Heat-Shock Proteins/antagonists & inhibitors ; Isoxazoles/pharmacology ; Mice ; Myelin Sheath/drug effects ; Myelin Sheath/pathology ; Nerve Fibers, Myelinated/drug effects ; Nerve Fibers, Myelinated/pathology ; Resorcinols/pharmacology
Chemical Substances	5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide ; HSP90 Heat-Shock Proteins ; Isoxazoles ; Resorcinols
Language	English
Publishing date	2019-05-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.9b00105
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