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ID 115009
Author
Yamaguchi, Junji Juntendo University
Suzuki, Chigure Juntendo University
Nanao, Tomohisa Tokyo University of Science
Kakuta, Soichirou Juntendo University
Ozawa, Kentarou Nara Medical University
Tanida, Isei Juntendo University
Sunabori, Takehiko Juntendo University
Komatsu, Masaaki Niigata University
Tanaka, Keiji Tokyo Metropolitan Institute of Medical Science
Aoki, Shigeki Juntendo University
Sakimura, Kenji Niigata University
Uchiyama, Yasuo Juntendo University
Keywords
Atg9a
axon
conditional knockout mice
degeneration
diffusion tensor MRI
dysgenesis of commissure fibers
nonselective autophagy
selective autophagy
spongiosis
Content Type
Journal Article
Description
Conditional knockout mice for Atg9a, specifically in brain tissue, were generated to understand the roles of ATG9A in the neural tissue cells. The mice were born normally, but half of them died within one wk, and none lived beyond 4 wk of age. SQSTM1/p62 and NBR1, receptor proteins for selective autophagy, together with ubiquitin, accumulated in Atg9a-deficient neurosoma at postnatal d 15 (P15), indicating an inhibition of autophagy, whereas these proteins were significantly decreased at P28, as evidenced by immunohistochemistry, electron microscopy and western blot. Conversely, degenerative changes such as spongiosis of nerve fiber tracts proceeded in axons and their terminals that were occupied with aberrant membrane structures and amorphous materials at P28, although no clear-cut degenerative change was detected in neuronal cell bodies. Different from autophagy, diffusion tensor magnetic resonance imaging and histological observations revealed Atg9a-deficiency-induced dysgenesis of the corpus callosum and anterior commissure. As for the neurite extensions of primary cultured neurons, the neurite outgrowth after 3 d culturing was significantly impaired in primary neurons from atg9a-KO mouse brains, but not in those from atg7-KO and atg16l1-KO brains. Moreover, this tendency was also confirmed in Atg9a-knockdown neurons under an atg7-KO background, indicating the role of ATG9A in the regulation of neurite outgrowth that is independent of autophagy. These results suggest that Atg9a deficiency causes progressive degeneration in the axons and their terminals, but not in neuronal cell bodies, where the degradations of SQSTM1/p62 and NBR1 were insufficiently suppressed. Moreover, the deletion of Atg9a impaired nerve fiber tract formation.
Journal Title
Autophagy
ISSN
15548627
15548635
NCID
AA12157457
AA12814026
Publisher
Taylor & Francis
Volume
14
Issue
5
Start Page
764
End Page
777
Published Date
2018-03-06
Rights
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
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DOI (Published Version)
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language
eng
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departments
Institute of Advanced Medical Sciences