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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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Jones JR,Kong L,Hanna MG 4th,Hoffman B,Krencik R,Bradley R,Hagemann T,Choi J,Doers M,Dubovis M,Sherafat MA,Bhattacharyya A,Kendziorski C,Audhya A,Messing A,Zhang SC

doi

10.1016/j.celrep.2018.09.083

subject

Has Abstract

pub_date

2018-10-23 00:00:00

pages

947-958.e4

issue

4

issn

2211-1247

pii

S2211-1247(18)31543-2

journal_volume

25

pub_type

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