Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells

Ebrahimi‐Fakhari, Darius; Wahlster, Lara; Bartz, Fabian; Werenbeck-Ueding, Jennifer; Praggastis, Maria; Zhang, Jessie; Joggerst-Thomalla, Brigitte; Theiß, Susanne; Grimm, Dirk; Ory, Daniel S.; Runz, Heiko

doi:10.1093/hmg/ddw204

Cited by 85 publications

(103 citation statements)

References 47 publications

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“…A compensatory overexpression of NPC1-I1061T, in transgenic NPC1 mouse and cat models, was able to provide a partial correction of the disease phenotype [16]. In agreement with these data, it has also been shown that pharmacological treatments that lead to upregulation of NPC1 variant expression, including ryanodine receptor antagonists [17], treatment with oxysterols that bind to and stabilize NPC1 [18], reduced expression of TMEM97 [19], and HDAC inhibitors [20], partially abrogate the NPC1-I1061T phenotype in heterologous cell and patient fibroblast models. These findings highlight that modulation of the local folding and signaling environment can facilitate disease correction [21][22][23][24].…”

Section: Introductionsupporting

confidence: 59%

Managing the Spatial Covariance of Genetic Diversity in Niemann-Pick C1 Through Modulation of the Hsp70 Chaperone System

Wang

Scott

et al. 2018

Preprint

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Genetic diversity provides a rich repository for understanding the role of proteostasis in the management of the protein fold to allow biology to evolve through variation in the population and in response to the environment. Failure in proteostasis can trigger multiple disease states affecting both human health and lifespan. Niemann-Pick C (NPC) disease is a genetic disorder mainly caused by mutations in NPC1, a multi-spanning transmembrane protein that is trafficked through the exocytic pathway to late endosomes and lysosomes (LE/Ly) to manage cholesterol homeostasis. Proteostatic defects triggered by >600 NPC1 variants found in the human population inhibit export of NPC1 protein from ER or function in downstream LE/Ly, leading to accumulation of cholesterol and rapid onset neurodegeneration in childhood for most patients. We now show that chemical allosteric inhibitors, such as JG98, targeting the cytosolic Hsp70 chaperone/co-chaperone complex improves the trafficking and stability of NPC1 variants with diverse NPC1 genotypes. By exploiting the knowledge-base of NPC1 variants found in the world-wide patient population using Variation Spatial Profiling (VSP), a Gaussianprocess based machine learning (ML) approach, we show how the Hsp70 chaperone system alters the spatial covariance (SCV) tolerance of the ER and the SCV set-points for each residue of the NPC1 polypeptide chain differentially to improve trafficking efficiency and post-ER stability for variants distributed across the entire NPC1 polypeptide. The impact of JG98 is supported by the observation that silencing of Hsp70 specific nucleotide exchange factors (NEF) (BCL-anthogene (BAG) family) cochaperones significantly improve the folding status of NPC1 variants. Together, these studies suggest that targeting the cytosolic Hsp70 system to adjust the SCV tolerance of the proteostasis network can improve recognition of the plasticity of the NPC1 fold found in the disease population for trafficking to the LE/Ly compartments.

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Section: Introductionsupporting

confidence: 59%

Managing the Spatial Covariance of Genetic Diversity in Niemann-Pick C1 Through Modulation of the Hsp70 Chaperone System

Wang

Scott

et al. 2018

Preprint

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“…11,12 σ 2R/TMEM97 has long been associated with cancer, 13,14 and it is increasingly being implicated in cellular processes relevant to a variety of CNS disorders, 10,15 including Alzheimer's disease (AD), 8,16–18 schizophrenia, 10 anxiety, pain, 19 and Niemann-Pick disease. 12 …”

Section: Introductionmentioning

confidence: 99%

High-Content Microfluidic Screening Platform Used To Identify σ2R/Tmem97 Binding Ligands that Reduce Age-Dependent Neurodegeneration in C. elegans SC_APP Model

Mondal

Hegarty

Sahn

et al. 2018

ACS Chem. Neurosci.

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The nematode Caenorhabditis elegans, with tractable genetics and a well-defined nervous system, provides a unique whole-animal model system to identify novel drug targets and therapies for neurodegenerative diseases. Large-scale drug or target screens in models that recapitulate the subtle age- and cell-specific aspects of neurodegenerative diseases are limited by a technological requirement for high-throughput analysis of neuronal morphology. Recently, we developed a single-copy model of amyloid precursor protein (SC_APP) induced neurodegeneration that exhibits progressive degeneration of select cholinergic neurons. Our previous work with this model suggests that small molecule ligands of the sigma 2 receptor (σ2R), which was recently cloned and identified as transmembrane protein 97 (TMEM97), are neuroprotective. To determine structure–activity relationships for unexplored chemical space in our σ2R/Tmem97 ligand collection, we developed an in vivo high-content screening (HCS) assay to identify potential drug leads. The HCS assay uses our recently developed large-scale microfluidic immobilization chip and automated imaging platform. We discovered norbenzomorphans that reduced neurodegeneration in our C. elegans model, including two compounds that demonstrated significant neuroprotective activity at multiple doses. These findings provide further evidence that σ2R/Tmem97-binding norbenzomorphans may represent a new drug class for treating neurodegenerative diseases.

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“…After decades of studies, cholesterol biology remains inadequately understood, in particular, the regulations involving lysosomes, which distribute cholesterol to other organelles 1 . Recently, TMEM97 was reported as a novel player in cholesterol transport 2,3 . An ER resident protein, TMEM97 can translocate to the lysosomal membrane where it appears to attenuate the activity of NPC1 (Niemann-Pick disease, type C) 3 , the transporter that "pumps" cholesterol out of the lysosome.…”

Section: Introductionmentioning

confidence: 99%

BRD2 regulation of sigma-2 receptor expression upon cytosolic cholesterol deprivation

Shen

Xie

et al. 2019

Preprint

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Traditionally a pharmacologic target for antipsychotic treatment, the sigma-2 receptor (S2R) was recently implicated in cholesterol homeostasis. Here we investigated the transcriptional regulation of S2R by the Bromo/ExtraTerminal epigenetic reader family (BETs, including BRD2, 3, 4) upon cholesterol perturbation.Cytosolic cholesterol deprivation was induced using an export blocker of lysosomal cholesterol in ARPE19 cells. This condition upregulated mRNA and protein levels of S2R, and of SREBP2 but not SREBP1, transcription factors key to cholesterol/fatty acid metabolism. Silencing BRD2 but not BRD4 (though widely deemed as a master regulator) or BRD3 prevented S2R upregulation induced by cholesterol deprivation. Silencing SREBP2 but not SREBP1 diminished S2R expression. Furthermore, BRD2 co-immunoprecipitated with the SREBP2 transcriptionactive N-terminal domain, and chromatin immunoprecipitation-qPCR showed a BRD2 occupancy at the S2R gene promoter.In summary, this study reveals a novel BRD2/SREBP2 cooperative regulation of S2R transcription in response to cytosolic cholesterol deprivation, thus shedding new light on epigenetic control of cholesterol biology.

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Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells

Cited by 85 publications

References 47 publications

Managing the Spatial Covariance of Genetic Diversity in Niemann-Pick C1 Through Modulation of the Hsp70 Chaperone System

Managing the Spatial Covariance of Genetic Diversity in Niemann-Pick C1 Through Modulation of the Hsp70 Chaperone System

High-Content Microfluidic Screening Platform Used To Identify σ2R/Tmem97 Binding Ligands that Reduce Age-Dependent Neurodegeneration in C. elegans SC_APP Model

BRD2 regulation of sigma-2 receptor expression upon cytosolic cholesterol deprivation

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