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@ARTICLE{Hagiwara:142899,
author = {D. Hagiwara$^*$ and V. Grinevich$^*$ and H. Arima},
title = {{A} novel mechanism of autophagy-associated cell death of
vasopressin neurons in familial neurohypophysial diabetes
insipidus.},
journal = {Cell $\&$ tissue research},
volume = {375},
number = {1},
issn = {1432-0878},
address = {Heidelberg},
publisher = {Springer},
reportid = {DKFZ-2019-00529},
pages = {259 - 266},
year = {2019},
abstract = {Familial neurohypophysial diabetes insipidus (FNDI),
characterized by delayed-onset progressive polyuria and loss
of arginine vasopressin (AVP) neuron, is an autosomal
dominant disorder caused by AVP gene mutations. We
previously generated a knock-in mouse model for FNDI, which
recapitulated the phenotype of human FNDI. To address the
mechanisms underlying AVP neuron loss, we subjected FNDI
mice to intermittent water deprivation, which accelerated
the phenotype and induced AVP neuron loss within a relative
short period. Electron microscopic analyses revealed that
aggregates were confined to a sub-compartment of the
endoplasmic reticulum (ER), ER-associated compartment
(ERAC), in AVP neurons of FNDI mice under normal conditions.
In contrast, aggregates scattered throughout the dilated ER
lumen, and phagophores, autophagosome precursors, emerged
and surrounded the ER containing scattered aggregates in
FNDI mice subjected to water deprivation for 4 weeks,
suggesting that failure of ERAC formation leads to autophagy
induction for degradation of aggregates. Furthermore, the
cytoplasm was entirely occupied with large vacuoles in AVP
neurons of FNDI mice subjected to water deprivation for
12 weeks, at which stage $30-40\%$ of AVP neurons were
lost. Our data demonstrated that although autophagy should
primarily be a protective mechanism, continuous autophagy
leads to gradual loss of organelles including ER, resulting
in autophagy-associated cell death of AVP neurons in FNDI
mice.},
subtyp = {Review Article},
cin = {V078},
ddc = {610},
cid = {I:(DE-He78)V078-20160331},
pnm = {319H - Addenda (POF3-319H)},
pid = {G:(DE-HGF)POF3-319H},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:29961215},
doi = {10.1007/s00441-018-2872-4},
url = {https://inrepo02.dkfz.de/record/142899},
}