Mutations in GFAP Disrupt the Distribution and Function of Organelles in Human Astrocytes

Research output: Contribution to journalArticle

Jeffrey R. Jones, Linghai Kong, Michael G. Hanna, Brianna Hoffman, Robert C. Krencik, Robert Bradley, Tracy Hagemann, Jeea Choi, Matthew Doers, Marina Dubovis, Mohammad Amin Sherafat, Anita Bhattacharyya, Christina Kendziorski, Anjon Audhya, Albee Messing, Su Chun Zhang

How mutations in glial fibrillary acidic protein (GFAP) cause Alexander disease (AxD) remains elusive. We generated iPSCs from two AxD patients and corrected the GFAP mutations to examine the effects of mutant GFAP on human astrocytes. AxD astrocytes displayed GFAP aggregates, recapitulating the pathological hallmark of AxD. RNA sequencing implicated the endoplasmic reticulum, vesicle regulation, and cellular metabolism. Corroborating this analysis, we observed enlarged and heterogeneous morphology coupled with perinuclear localization of endoplasmic reticulum and lysosomes in AxD astrocytes. Functionally, AxD astrocytes showed impaired extracellular ATP release, which is responsible for attenuated calcium wave propagation. These results reveal that AxD-causing mutations in GFAP disrupt intracellular vesicle regulation and impair astrocyte secretion, resulting in astrocyte dysfunction and AxD pathogenesis. Jones et al. study the structure function relationship of GFAP on astrocytes using Alexander disease patient-derived induced pluripotent stem cells. Mutations in GFAP result in mislocalization of organelles and functional consequences such as reduced ATP release and attenuated calcium wave propagation. Genetic correction of mutant GFAP rescues these defects.

Original languageEnglish (US)
Pages (from-to)947-958.e4
JournalCell Reports
Volume25
Issue number4
DOIs
StatePublished - Oct 23 2018

PMID: 30355500

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Mutations in GFAP Disrupt the Distribution and Function of Organelles in Human Astrocytes. / Jones, Jeffrey R.; Kong, Linghai; Hanna, Michael G.; Hoffman, Brianna; Krencik, Robert C.; Bradley, Robert; Hagemann, Tracy; Choi, Jeea; Doers, Matthew; Dubovis, Marina; Sherafat, Mohammad Amin; Bhattacharyya, Anita; Kendziorski, Christina; Audhya, Anjon; Messing, Albee; Zhang, Su Chun.

In: Cell Reports, Vol. 25, No. 4, 23.10.2018, p. 947-958.e4.

Research output: Contribution to journalArticle

Harvard

Jones, JR, Kong, L, Hanna, MG, Hoffman, B, Krencik, RC, Bradley, R, Hagemann, T, Choi, J, Doers, M, Dubovis, M, Sherafat, MA, Bhattacharyya, A, Kendziorski, C, Audhya, A, Messing, A & Zhang, SC 2018, 'Mutations in GFAP Disrupt the Distribution and Function of Organelles in Human Astrocytes' Cell Reports, vol. 25, no. 4, pp. 947-958.e4. https://doi.org/10.1016/j.celrep.2018.09.083

APA

Jones, J. R., Kong, L., Hanna, M. G., Hoffman, B., Krencik, R. C., Bradley, R., ... Zhang, S. C. (2018). Mutations in GFAP Disrupt the Distribution and Function of Organelles in Human Astrocytes. Cell Reports, 25(4), 947-958.e4. https://doi.org/10.1016/j.celrep.2018.09.083

Vancouver

Jones JR, Kong L, Hanna MG, Hoffman B, Krencik RC, Bradley R et al. Mutations in GFAP Disrupt the Distribution and Function of Organelles in Human Astrocytes. Cell Reports. 2018 Oct 23;25(4):947-958.e4. https://doi.org/10.1016/j.celrep.2018.09.083

Author

Jones, Jeffrey R. ; Kong, Linghai ; Hanna, Michael G. ; Hoffman, Brianna ; Krencik, Robert C. ; Bradley, Robert ; Hagemann, Tracy ; Choi, Jeea ; Doers, Matthew ; Dubovis, Marina ; Sherafat, Mohammad Amin ; Bhattacharyya, Anita ; Kendziorski, Christina ; Audhya, Anjon ; Messing, Albee ; Zhang, Su Chun. / Mutations in GFAP Disrupt the Distribution and Function of Organelles in Human Astrocytes. In: Cell Reports. 2018 ; Vol. 25, No. 4. pp. 947-958.e4.

BibTeX

@article{78c5566b80dc4a8298c6d5a25f5bdff8,
title = "Mutations in GFAP Disrupt the Distribution and Function of Organelles in Human Astrocytes",
abstract = "How mutations in glial fibrillary acidic protein (GFAP) cause Alexander disease (AxD) remains elusive. We generated iPSCs from two AxD patients and corrected the GFAP mutations to examine the effects of mutant GFAP on human astrocytes. AxD astrocytes displayed GFAP aggregates, recapitulating the pathological hallmark of AxD. RNA sequencing implicated the endoplasmic reticulum, vesicle regulation, and cellular metabolism. Corroborating this analysis, we observed enlarged and heterogeneous morphology coupled with perinuclear localization of endoplasmic reticulum and lysosomes in AxD astrocytes. Functionally, AxD astrocytes showed impaired extracellular ATP release, which is responsible for attenuated calcium wave propagation. These results reveal that AxD-causing mutations in GFAP disrupt intracellular vesicle regulation and impair astrocyte secretion, resulting in astrocyte dysfunction and AxD pathogenesis. Jones et al. study the structure function relationship of GFAP on astrocytes using Alexander disease patient-derived induced pluripotent stem cells. Mutations in GFAP result in mislocalization of organelles and functional consequences such as reduced ATP release and attenuated calcium wave propagation. Genetic correction of mutant GFAP rescues these defects.",
keywords = "Alexander disease, CRISPR, endoplasmic reticulum, iPSC, lysosome",
author = "Jones, {Jeffrey R.} and Linghai Kong and Hanna, {Michael G.} and Brianna Hoffman and Krencik, {Robert C.} and Robert Bradley and Tracy Hagemann and Jeea Choi and Matthew Doers and Marina Dubovis and Sherafat, {Mohammad Amin} and Anita Bhattacharyya and Christina Kendziorski and Anjon Audhya and Albee Messing and Zhang, {Su Chun}",
note = "Copyright {\circledC} 2018 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2018",
month = "10",
day = "23",
doi = "10.1016/j.celrep.2018.09.083",
language = "English (US)",
volume = "25",
pages = "947--958.e4",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
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RIS

TY - JOUR

T1 - Mutations in GFAP Disrupt the Distribution and Function of Organelles in Human Astrocytes

AU - Jones, Jeffrey R.

AU - Kong, Linghai

AU - Hanna, Michael G.

AU - Hoffman, Brianna

AU - Krencik, Robert C.

AU - Bradley, Robert

AU - Hagemann, Tracy

AU - Choi, Jeea

AU - Doers, Matthew

AU - Dubovis, Marina

AU - Sherafat, Mohammad Amin

AU - Bhattacharyya, Anita

AU - Kendziorski, Christina

AU - Audhya, Anjon

AU - Messing, Albee

AU - Zhang, Su Chun

N1 - Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2018/10/23

Y1 - 2018/10/23

N2 - How mutations in glial fibrillary acidic protein (GFAP) cause Alexander disease (AxD) remains elusive. We generated iPSCs from two AxD patients and corrected the GFAP mutations to examine the effects of mutant GFAP on human astrocytes. AxD astrocytes displayed GFAP aggregates, recapitulating the pathological hallmark of AxD. RNA sequencing implicated the endoplasmic reticulum, vesicle regulation, and cellular metabolism. Corroborating this analysis, we observed enlarged and heterogeneous morphology coupled with perinuclear localization of endoplasmic reticulum and lysosomes in AxD astrocytes. Functionally, AxD astrocytes showed impaired extracellular ATP release, which is responsible for attenuated calcium wave propagation. These results reveal that AxD-causing mutations in GFAP disrupt intracellular vesicle regulation and impair astrocyte secretion, resulting in astrocyte dysfunction and AxD pathogenesis. Jones et al. study the structure function relationship of GFAP on astrocytes using Alexander disease patient-derived induced pluripotent stem cells. Mutations in GFAP result in mislocalization of organelles and functional consequences such as reduced ATP release and attenuated calcium wave propagation. Genetic correction of mutant GFAP rescues these defects.

AB - How mutations in glial fibrillary acidic protein (GFAP) cause Alexander disease (AxD) remains elusive. We generated iPSCs from two AxD patients and corrected the GFAP mutations to examine the effects of mutant GFAP on human astrocytes. AxD astrocytes displayed GFAP aggregates, recapitulating the pathological hallmark of AxD. RNA sequencing implicated the endoplasmic reticulum, vesicle regulation, and cellular metabolism. Corroborating this analysis, we observed enlarged and heterogeneous morphology coupled with perinuclear localization of endoplasmic reticulum and lysosomes in AxD astrocytes. Functionally, AxD astrocytes showed impaired extracellular ATP release, which is responsible for attenuated calcium wave propagation. These results reveal that AxD-causing mutations in GFAP disrupt intracellular vesicle regulation and impair astrocyte secretion, resulting in astrocyte dysfunction and AxD pathogenesis. Jones et al. study the structure function relationship of GFAP on astrocytes using Alexander disease patient-derived induced pluripotent stem cells. Mutations in GFAP result in mislocalization of organelles and functional consequences such as reduced ATP release and attenuated calcium wave propagation. Genetic correction of mutant GFAP rescues these defects.

KW - Alexander disease

KW - CRISPR

KW - endoplasmic reticulum

KW - iPSC

KW - lysosome

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U2 - 10.1016/j.celrep.2018.09.083

DO - 10.1016/j.celrep.2018.09.083

M3 - Article

VL - 25

SP - 947-958.e4

JO - Cell Reports

T2 - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 4

ER -

ID: 41891962