PMP22 Regulates Cholesterol Trafficking and ABCA1-Mediated Cholesterol Efflux

Ye Zhou, Joshua R. Miles, Hagai Tavori, Min Lin, Habibeh Khoshbouei, David R. Borchelt, Hannah Bazick, Gary E. Landreth, Sooyeon Lee, Sergio Fazio, Lucia Notterpek

    Research output: Contribution to journalArticle

    1 Citation (Scopus)

    Abstract

    The absence of functional peripheral myelin protein 22 (PMP22) is associated with shortened lifespan in rodents and severe peripheral nerve myelin abnormalities in several species including humans. Schwann cells and nerves from PMP22 knock-out (KO) mice show deranged cholesterol distribution and aberrant lipid raft morphology, supporting an unrecognized role for PMP22 in cellular lipid metabolism. To examine the mechanisms underlying these abnormalities, we studied Schwann cells and nerves from male and female PMP22 KO mice. Whole-cell current-clamp recordings in cultured Schwann cells revealed increased membrane capacitance and decreased membrane resistance in the absence of PMP22, which was consistent with a reduction in membrane cholesterol. Nerves from PMP22-deficient mice contained abnormal lipid droplets, with both mRNA and protein levels of apolipoprotein E (apoE) and ATP-binding cassette transporter A1 (ABCA1) being highly upregulated. Despite the upregulation of ABCA1 and apoE, the absence of PMP22 resulted in reduced localization of the transporter to the cell membrane and diminished secretion of apoE. The absence of PMP22 also impaired ABCA1-mediated cholesterol efflux capacity. In nerves from ABCA1 KO mice, the expression of PMP22 was significantly elevated and the subcellular processing of the overproduced protein was aberrant. In wild-type samples, double immunolabeling identified overlapping distribution of PMP22 and ABCA1 at the Schwann cell plasma membrane and the two proteins were coimmunoprecipitated from Schwann cell and nerve lysates. Together, these results reveal a novel role for PMP22 in regulating lipid metabolism and cholesterol trafficking through functional interaction with the cholesterol efflux regulatory protein ABCA1.SIGNIFICANCE STATEMENT Understanding the subcellular events that underlie abnormal myelin formation in hereditary neuropathies is critical for advancing therapy development. Peripheral myelin protein 22 (PMP22) is an essential peripheral myelin protein because its genetic abnormalities account for ∼80% of hereditary neuropathies. Here, we demonstrate that in the absence of PMP22, the cellular and electrophysiological properties of the Schwann cells' plasma membrane are altered and cholesterol trafficking and lipid homeostasis are perturbed. The molecular mechanisms for these abnormalities involve a functional interplay among PMP22, cholesterol, apolipoprotein E, and the major cholesterol-efflux transporter protein ATP-binding cassette transporter A1 (ABCA1). These findings establish a critical role for PMP22 in the maintenance of cholesterol homeostasis in Schwann cells.

    Original languageEnglish (US)
    Pages (from-to)5404-5418
    Number of pages15
    JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience
    Volume39
    Issue number27
    DOIs
    StatePublished - Jul 3 2019

    Fingerprint

    Myelin Proteins
    ATP-Binding Cassette Transporters
    Cholesterol
    Schwann Cells
    Apolipoproteins E
    Cell Membrane
    Peripheral Nerves
    Knockout Mice
    Myelin Sheath
    Lipid Metabolism
    Protein Binding
    Membranes
    ATP Binding Cassette Transporter 1
    Homeostasis
    Lipids

    Keywords

    • apoE
    • ATP-binding cassette transporter 1
    • cholesterol efflux
    • hereditary neuropathy
    • peripheral myelin protein 22
    • Schwann cell

    ASJC Scopus subject areas

    • Neuroscience(all)

    Cite this

    PMP22 Regulates Cholesterol Trafficking and ABCA1-Mediated Cholesterol Efflux. / Zhou, Ye; Miles, Joshua R.; Tavori, Hagai; Lin, Min; Khoshbouei, Habibeh; Borchelt, David R.; Bazick, Hannah; Landreth, Gary E.; Lee, Sooyeon; Fazio, Sergio; Notterpek, Lucia.

    In: The Journal of neuroscience : the official journal of the Society for Neuroscience, Vol. 39, No. 27, 03.07.2019, p. 5404-5418.

    Research output: Contribution to journalArticle

    Zhou, Y, Miles, JR, Tavori, H, Lin, M, Khoshbouei, H, Borchelt, DR, Bazick, H, Landreth, GE, Lee, S, Fazio, S & Notterpek, L 2019, 'PMP22 Regulates Cholesterol Trafficking and ABCA1-Mediated Cholesterol Efflux', The Journal of neuroscience : the official journal of the Society for Neuroscience, vol. 39, no. 27, pp. 5404-5418. https://doi.org/10.1523/JNEUROSCI.2942-18.2019
    Zhou, Ye ; Miles, Joshua R. ; Tavori, Hagai ; Lin, Min ; Khoshbouei, Habibeh ; Borchelt, David R. ; Bazick, Hannah ; Landreth, Gary E. ; Lee, Sooyeon ; Fazio, Sergio ; Notterpek, Lucia. / PMP22 Regulates Cholesterol Trafficking and ABCA1-Mediated Cholesterol Efflux. In: The Journal of neuroscience : the official journal of the Society for Neuroscience. 2019 ; Vol. 39, No. 27. pp. 5404-5418.
    @article{c9f26420613e4282b3a6470a2f79e3bd,
    title = "PMP22 Regulates Cholesterol Trafficking and ABCA1-Mediated Cholesterol Efflux",
    abstract = "The absence of functional peripheral myelin protein 22 (PMP22) is associated with shortened lifespan in rodents and severe peripheral nerve myelin abnormalities in several species including humans. Schwann cells and nerves from PMP22 knock-out (KO) mice show deranged cholesterol distribution and aberrant lipid raft morphology, supporting an unrecognized role for PMP22 in cellular lipid metabolism. To examine the mechanisms underlying these abnormalities, we studied Schwann cells and nerves from male and female PMP22 KO mice. Whole-cell current-clamp recordings in cultured Schwann cells revealed increased membrane capacitance and decreased membrane resistance in the absence of PMP22, which was consistent with a reduction in membrane cholesterol. Nerves from PMP22-deficient mice contained abnormal lipid droplets, with both mRNA and protein levels of apolipoprotein E (apoE) and ATP-binding cassette transporter A1 (ABCA1) being highly upregulated. Despite the upregulation of ABCA1 and apoE, the absence of PMP22 resulted in reduced localization of the transporter to the cell membrane and diminished secretion of apoE. The absence of PMP22 also impaired ABCA1-mediated cholesterol efflux capacity. In nerves from ABCA1 KO mice, the expression of PMP22 was significantly elevated and the subcellular processing of the overproduced protein was aberrant. In wild-type samples, double immunolabeling identified overlapping distribution of PMP22 and ABCA1 at the Schwann cell plasma membrane and the two proteins were coimmunoprecipitated from Schwann cell and nerve lysates. Together, these results reveal a novel role for PMP22 in regulating lipid metabolism and cholesterol trafficking through functional interaction with the cholesterol efflux regulatory protein ABCA1.SIGNIFICANCE STATEMENT Understanding the subcellular events that underlie abnormal myelin formation in hereditary neuropathies is critical for advancing therapy development. Peripheral myelin protein 22 (PMP22) is an essential peripheral myelin protein because its genetic abnormalities account for ∼80{\%} of hereditary neuropathies. Here, we demonstrate that in the absence of PMP22, the cellular and electrophysiological properties of the Schwann cells' plasma membrane are altered and cholesterol trafficking and lipid homeostasis are perturbed. The molecular mechanisms for these abnormalities involve a functional interplay among PMP22, cholesterol, apolipoprotein E, and the major cholesterol-efflux transporter protein ATP-binding cassette transporter A1 (ABCA1). These findings establish a critical role for PMP22 in the maintenance of cholesterol homeostasis in Schwann cells.",
    keywords = "apoE, ATP-binding cassette transporter 1, cholesterol efflux, hereditary neuropathy, peripheral myelin protein 22, Schwann cell",
    author = "Ye Zhou and Miles, {Joshua R.} and Hagai Tavori and Min Lin and Habibeh Khoshbouei and Borchelt, {David R.} and Hannah Bazick and Landreth, {Gary E.} and Sooyeon Lee and Sergio Fazio and Lucia Notterpek",
    year = "2019",
    month = "7",
    day = "3",
    doi = "10.1523/JNEUROSCI.2942-18.2019",
    language = "English (US)",
    volume = "39",
    pages = "5404--5418",
    journal = "Journal of Neuroscience",
    issn = "0270-6474",
    publisher = "Society for Neuroscience",
    number = "27",

    }

    TY - JOUR

    T1 - PMP22 Regulates Cholesterol Trafficking and ABCA1-Mediated Cholesterol Efflux

    AU - Zhou, Ye

    AU - Miles, Joshua R.

    AU - Tavori, Hagai

    AU - Lin, Min

    AU - Khoshbouei, Habibeh

    AU - Borchelt, David R.

    AU - Bazick, Hannah

    AU - Landreth, Gary E.

    AU - Lee, Sooyeon

    AU - Fazio, Sergio

    AU - Notterpek, Lucia

    PY - 2019/7/3

    Y1 - 2019/7/3

    N2 - The absence of functional peripheral myelin protein 22 (PMP22) is associated with shortened lifespan in rodents and severe peripheral nerve myelin abnormalities in several species including humans. Schwann cells and nerves from PMP22 knock-out (KO) mice show deranged cholesterol distribution and aberrant lipid raft morphology, supporting an unrecognized role for PMP22 in cellular lipid metabolism. To examine the mechanisms underlying these abnormalities, we studied Schwann cells and nerves from male and female PMP22 KO mice. Whole-cell current-clamp recordings in cultured Schwann cells revealed increased membrane capacitance and decreased membrane resistance in the absence of PMP22, which was consistent with a reduction in membrane cholesterol. Nerves from PMP22-deficient mice contained abnormal lipid droplets, with both mRNA and protein levels of apolipoprotein E (apoE) and ATP-binding cassette transporter A1 (ABCA1) being highly upregulated. Despite the upregulation of ABCA1 and apoE, the absence of PMP22 resulted in reduced localization of the transporter to the cell membrane and diminished secretion of apoE. The absence of PMP22 also impaired ABCA1-mediated cholesterol efflux capacity. In nerves from ABCA1 KO mice, the expression of PMP22 was significantly elevated and the subcellular processing of the overproduced protein was aberrant. In wild-type samples, double immunolabeling identified overlapping distribution of PMP22 and ABCA1 at the Schwann cell plasma membrane and the two proteins were coimmunoprecipitated from Schwann cell and nerve lysates. Together, these results reveal a novel role for PMP22 in regulating lipid metabolism and cholesterol trafficking through functional interaction with the cholesterol efflux regulatory protein ABCA1.SIGNIFICANCE STATEMENT Understanding the subcellular events that underlie abnormal myelin formation in hereditary neuropathies is critical for advancing therapy development. Peripheral myelin protein 22 (PMP22) is an essential peripheral myelin protein because its genetic abnormalities account for ∼80% of hereditary neuropathies. Here, we demonstrate that in the absence of PMP22, the cellular and electrophysiological properties of the Schwann cells' plasma membrane are altered and cholesterol trafficking and lipid homeostasis are perturbed. The molecular mechanisms for these abnormalities involve a functional interplay among PMP22, cholesterol, apolipoprotein E, and the major cholesterol-efflux transporter protein ATP-binding cassette transporter A1 (ABCA1). These findings establish a critical role for PMP22 in the maintenance of cholesterol homeostasis in Schwann cells.

    AB - The absence of functional peripheral myelin protein 22 (PMP22) is associated with shortened lifespan in rodents and severe peripheral nerve myelin abnormalities in several species including humans. Schwann cells and nerves from PMP22 knock-out (KO) mice show deranged cholesterol distribution and aberrant lipid raft morphology, supporting an unrecognized role for PMP22 in cellular lipid metabolism. To examine the mechanisms underlying these abnormalities, we studied Schwann cells and nerves from male and female PMP22 KO mice. Whole-cell current-clamp recordings in cultured Schwann cells revealed increased membrane capacitance and decreased membrane resistance in the absence of PMP22, which was consistent with a reduction in membrane cholesterol. Nerves from PMP22-deficient mice contained abnormal lipid droplets, with both mRNA and protein levels of apolipoprotein E (apoE) and ATP-binding cassette transporter A1 (ABCA1) being highly upregulated. Despite the upregulation of ABCA1 and apoE, the absence of PMP22 resulted in reduced localization of the transporter to the cell membrane and diminished secretion of apoE. The absence of PMP22 also impaired ABCA1-mediated cholesterol efflux capacity. In nerves from ABCA1 KO mice, the expression of PMP22 was significantly elevated and the subcellular processing of the overproduced protein was aberrant. In wild-type samples, double immunolabeling identified overlapping distribution of PMP22 and ABCA1 at the Schwann cell plasma membrane and the two proteins were coimmunoprecipitated from Schwann cell and nerve lysates. Together, these results reveal a novel role for PMP22 in regulating lipid metabolism and cholesterol trafficking through functional interaction with the cholesterol efflux regulatory protein ABCA1.SIGNIFICANCE STATEMENT Understanding the subcellular events that underlie abnormal myelin formation in hereditary neuropathies is critical for advancing therapy development. Peripheral myelin protein 22 (PMP22) is an essential peripheral myelin protein because its genetic abnormalities account for ∼80% of hereditary neuropathies. Here, we demonstrate that in the absence of PMP22, the cellular and electrophysiological properties of the Schwann cells' plasma membrane are altered and cholesterol trafficking and lipid homeostasis are perturbed. The molecular mechanisms for these abnormalities involve a functional interplay among PMP22, cholesterol, apolipoprotein E, and the major cholesterol-efflux transporter protein ATP-binding cassette transporter A1 (ABCA1). These findings establish a critical role for PMP22 in the maintenance of cholesterol homeostasis in Schwann cells.

    KW - apoE

    KW - ATP-binding cassette transporter 1

    KW - cholesterol efflux

    KW - hereditary neuropathy

    KW - peripheral myelin protein 22

    KW - Schwann cell

    UR - http://www.scopus.com/inward/record.url?scp=85069273777&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=85069273777&partnerID=8YFLogxK

    U2 - 10.1523/JNEUROSCI.2942-18.2019

    DO - 10.1523/JNEUROSCI.2942-18.2019

    M3 - Article

    VL - 39

    SP - 5404

    EP - 5418

    JO - Journal of Neuroscience

    JF - Journal of Neuroscience

    SN - 0270-6474

    IS - 27

    ER -