Degradation of Alzheimer's amyloid fibrils by microglia requires delivery of CIC-7 to lysosomes
Majumdar, Amitabha ; Capetillo-Zarate, Estibaliz ; Cruz, Dana ; Gouras, Gunnar K. LU
and Maxfield, Frederick R.
(2011)
In Molecular Biology of the Cell
22(10).
p.1664-1676
- Abstract
Incomplete lysosomal acidification in microglia inhibits the degradation of fibrillar forms of Alzheimer's amyloid β peptide (fAβ). Here we show that in primary microglia a chloride transporter, ClC-7, is not delivered efficiently to lysosomes, causing incomplete lysosomal acidification. ClC-7 protein is synthesized by microglia but it is mistargeted and appears to be degraded by an endoplasmic reticulum-associated degradation pathway. Activation of microglia with macrophage colony-stimulating factor induces trafficking of ClC-7 to lysosomes, leading to lysosomal acidification and increased fAβ degradation. ClC-7 associates with another protein, Ostm1, which plays an important role in its correct lysosomal targeting. Expression of both... (More)
Incomplete lysosomal acidification in microglia inhibits the degradation of fibrillar forms of Alzheimer's amyloid β peptide (fAβ). Here we show that in primary microglia a chloride transporter, ClC-7, is not delivered efficiently to lysosomes, causing incomplete lysosomal acidification. ClC-7 protein is synthesized by microglia but it is mistargeted and appears to be degraded by an endoplasmic reticulum-associated degradation pathway. Activation of microglia with macrophage colony-stimulating factor induces trafficking of ClC-7 to lysosomes, leading to lysosomal acidification and increased fAβ degradation. ClC-7 associates with another protein, Ostm1, which plays an important role in its correct lysosomal targeting. Expression of both ClC-7 and Ostm1 is increased in activated microglia, which can account for the increased delivery of ClC-7 to lysosomes. Our findings suggest a novel mechanism of lysosomal pH regulation in activated microglia that is required for fAβ degradation.
(Less)
- author
- Majumdar, Amitabha
; Capetillo-Zarate, Estibaliz
; Cruz, Dana
; Gouras, Gunnar K.
LU
and Maxfield, Frederick R.
- publishing date
- 2011-05-15
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Molecular Biology of the Cell
- volume
- 22
- issue
- 10
- pages
- 1664 - 1676
- publisher
- American Society for Cell Biology
- external identifiers
-
- pmid:21441306
- scopus:79955970157
- ISSN
- 1059-1524
- DOI
- 10.1091/mbc.E10-09-0745
- language
- English
- LU publication?
- no
- id
- ff390d8a-8bda-40c6-a2b0-060065ed7b53
- date added to LUP
- 2020-02-20 14:14:39
- date last changed
- 2024-04-03 03:07:47
@article{ff390d8a-8bda-40c6-a2b0-060065ed7b53,
abstract = {{<p>Incomplete lysosomal acidification in microglia inhibits the degradation of fibrillar forms of Alzheimer's amyloid β peptide (fAβ). Here we show that in primary microglia a chloride transporter, ClC-7, is not delivered efficiently to lysosomes, causing incomplete lysosomal acidification. ClC-7 protein is synthesized by microglia but it is mistargeted and appears to be degraded by an endoplasmic reticulum-associated degradation pathway. Activation of microglia with macrophage colony-stimulating factor induces trafficking of ClC-7 to lysosomes, leading to lysosomal acidification and increased fAβ degradation. ClC-7 associates with another protein, Ostm1, which plays an important role in its correct lysosomal targeting. Expression of both ClC-7 and Ostm1 is increased in activated microglia, which can account for the increased delivery of ClC-7 to lysosomes. Our findings suggest a novel mechanism of lysosomal pH regulation in activated microglia that is required for fAβ degradation.</p>}},
author = {{Majumdar, Amitabha and Capetillo-Zarate, Estibaliz and Cruz, Dana and Gouras, Gunnar K. and Maxfield, Frederick R.}},
issn = {{1059-1524}},
language = {{eng}},
month = {{05}},
number = {{10}},
pages = {{1664--1676}},
publisher = {{American Society for Cell Biology}},
series = {{Molecular Biology of the Cell}},
title = {{Degradation of Alzheimer's amyloid fibrils by microglia requires delivery of CIC-7 to lysosomes}},
url = {{http://dx.doi.org/10.1091/mbc.E10-09-0745}},
doi = {{10.1091/mbc.E10-09-0745}},
volume = {{22}},
year = {{2011}},
}