Heat shock protein amplification improves cerebellar myelination in the Npc1nih mouse model

Gray, James; Fernández-Suárez, María E.; Falah, Maysa; Smith, David A.; Smith, Claire; Kaya, Ecem; Palmer, Ashley M.; Fog, Cathrine K.; Kirkegaard, Tove; Platt, Frances M.

doi:10.1016/j.ebiom.2022.104374

Cited by 8 publications

(5 citation statements)

References 66 publications

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“…The importance of heat shock proteins in NPC disease pathology has received more recognition recently. Several heat shock proteins have been studied as potential neuroprotective therapeutics in NPC disease . HSPB1 has been reported to modulate Purkinje neuron vulnerability in the mouse model of NPC disease by promoting neuronal survival through a mechanism that involves inhibition of apoptosis .…”

Section: Resultsmentioning

confidence: 99%

“…Several heat shock proteins have been studied as potential neuroprotective therapeutics in NPC disease. 80 HSPB1 has been reported to modulate Purkinje neuron vulnerability in the mouse model of NPC disease by promoting neuronal survival through a mechanism that involves inhibition of apoptosis. 81 Moreover, several HSP90 inhibitors have been shown to reduce cholesterol storage in NPC disease.…”

Section: Protein−protein Interactors Of Npc1 I1061tmentioning

confidence: 99%

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Endogenous Protein–Protein Interaction Network of the NPC Cholesterol Transporter 1 in the Cerebral Cortex

Javanshad,

Nguyen,

Azaria

et al. 2024

J. Proteome Res.

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NPC intracellular cholesterol transporter 1 (NPC1) is a multipass, transmembrane glycoprotein mostly recognized for its key role in facilitating cholesterol efflux. Mutations in the NPC1 gene result in Niemann-Pick disease, type C (NPC), a fatal, lysosomal storage disease. Due to the progressively expanding implications of NPC1-related disorders, we investigated endogenous NPC1 protein−protein interactions in the mouse cortex and human-derived iPSCs neuronal models of the disease through coimmunoprecipitation-coupled with LC-MS based proteomics. The current study investigated protein−protein interactions specific to the wild-type and the most prevalent NPC1 mutation (NPC1 I1061T ) while filtering out any protein interactor identified in the Npc1 −/− mouse model. Additionally, the results were matched across the two species to map the parallel interactome of wild-type and mutant NPC1 I1061T . Most of the identified wild-type NPC1 interactors were related to cytoskeleton organization, synaptic vesicle activity, and translation. We found many putative NPC1 interactors not previously reported, including two SCAR/WAVE complex proteins that regulate ARP 2/3 complex actin nucleation and multiple membrane proteins important for neuronal activity at synapse. Moreover, we identified proteins important in trafficking specific to wild-type and mutant NPC1 I1061T . Together, the findings are essential for a comprehensive understanding of NPC1 biological functions in addition to its classical role in sterol efflux.

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Section: Resultsmentioning

confidence: 99%

Section: Protein−protein Interactors Of Npc1 I1061tmentioning

confidence: 99%

Endogenous Protein–Protein Interaction Network of the NPC Cholesterol Transporter 1 in the Cerebral Cortex

Javanshad,

Nguyen,

Azaria

et al. 2024

J. Proteome Res.

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“…Regarding NPC disease, Arimoclomol-treated Npc1 −/− mice re-activated the stress response in their brains, reducing neurodegeneration and improving locomotor coordination, but did not provide a rescue effect in the liver 99 . The treatment also enhanced myelination 100 . Furthermore, arimoclomol significantly reduced lysosomal storage and the buildup of unesterified cholesterol in NPC1 human fibroblasts 101 .…”

Section: Arimoclomolmentioning

confidence: 85%

Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine

Las Heras,

Szenfeld,

Ballout

et al. 2023

npj Genom. Med.

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Niemann-Pick type C (NPC) disease is a lysosomal storage disease (LSD) characterized by the buildup of endo-lysosomal cholesterol and glycosphingolipids due to loss of function mutations in the NPC1 and NPC2 genes. NPC patients can present with a broad phenotypic spectrum, with differences at the age of onset, rate of progression, severity, organs involved, effects on the central nervous system, and even response to pharmacological treatments. This article reviews the phenotypic variation of NPC and discusses its possible causes, such as the remaining function of the defective protein, modifier genes, sex, environmental cues, and splicing factors, among others. We propose that these factors should be considered when designing or repurposing treatments for this disease. Despite its seeming complexity, this proposition is not far-fetched, considering the expanding interest in precision medicine and easier access to multi-omics technologies.

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“…Another approach is the use of a recombinant HSP70 (rHSP70), with which a reduction in GLS species was observed in peripheral organs and the CNS of NPC mice, possibly due to the increase in sphingolipid-degrading enzymes by the action of rHSP70 [24]. The beneficial effects of using Hsp70 enhancement (rhHSP70) and bimoclomol, an analog of arimoclomol, were also observed at the stage of myelination in the cerebellum due to normalization of the mature oligodendrocyte population and rescue of atrophy in the cerebellum, resulting in improved behavioral outcomes [46]. The use of arimoclomol was evaluated in patients in a double-blind, randomized, placebo-controlled phase II/III clinical trial.…”

Section: Folding By Heat Shock Proteinsmentioning

confidence: 99%

Alterations in Proteostasis Mechanisms in Niemann–Pick Type C Disease

Servín Muñoz,

Ortuño-Sahagún,

Griñán-Ferré

et al. 2024

IJMS

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Niemann–Pick Type C (NPC) represents an autosomal recessive disorder with an incidence rate of 1 in 150,000 live births, classified within lysosomal storage diseases (LSDs). The abnormal accumulation of unesterified cholesterol characterizes the pathophysiology of NPC. This phenomenon is not unique to NPC, as analogous accumulations have also been observed in Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative disorders. Interestingly, disturbances in the folding of the mutant protein NPC1 I1061T are accompanied by the aggregation of proteins such as hyperphosphorylated tau, α-synuclein, TDP-43, and β-amyloid peptide. These accumulations suggest potential disruptions in proteostasis, a regulatory process encompassing four principal mechanisms: synthesis, folding, maintenance of folding, and protein degradation. The dysregulation of these processes leads to excessive accumulation of abnormal proteins that impair cell function and trigger cytotoxicity. This comprehensive review delineates reported alterations across proteostasis mechanisms in NPC, encompassing changes in processes from synthesis to degradation. Additionally, it discusses therapeutic interventions targeting pharmacological facets of proteostasis in NPC. Noteworthy among these interventions is valproic acid, a histone deacetylase inhibitor (HDACi) that modulates acetylation during NPC1 synthesis. In addition, various therapeutic options addressing protein folding modulation, such as abiraterone acetate, DHBP, calnexin, and arimoclomol, are examined. Additionally, treatments impeding NPC1 degradation, exemplified by bortezomib and MG132, are explored as potential strategies. This review consolidates current knowledge on proteostasis dysregulation in NPC and underscores the therapeutic landscape targeting diverse facets of this intricate process.

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Heat shock protein amplification improves cerebellar myelination in the Npc1nih mouse model

Cited by 8 publications

References 66 publications

Endogenous Protein–Protein Interaction Network of the NPC Cholesterol Transporter 1 in the Cerebral Cortex

Endogenous Protein–Protein Interaction Network of the NPC Cholesterol Transporter 1 in the Cerebral Cortex

Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine

Alterations in Proteostasis Mechanisms in Niemann–Pick Type C Disease

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