Universität zu Köln

Stoffel, Wilhelm, Jenke, Britta, Schmidt-Soltau, Inga, Binczek, Erika, Brodesser, Susanne and Hammels, Ina (2018). SMPD3 deficiency perturbs neuronal proteostasis and causes progressive cognitive impairment. Cell Death Dis., 9. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-4889

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Abstract

Neutral sphingomyelinase smpd3 is most abundantly expressed in neurons of brain. The function of SMPD3 has remained elusive. Here, we report a pathogenetic nexus between absence of SMPD3 in the Golgi compartment (GC) of neurons of the smpd3-/- mouse brain, inhibition of Golgi vesicular protein transport and progressive cognitive impairment. Absence of SMPD3 activity in the Golgi sphingomyelin cycle impedes remodeling of the lipid bilayer, essential for budding and multivesicular body formation. Importantly, we show that inhibition of the Golgi vesicular protein transport causes accumulation of neurotoxic proteins APP, A beta and phosphorylated Tau, dysproteostasis, unfolded protein response, and apoptosis, which ultimately manifests in progressive cognitive decline, similar to the pathognomonic signatures of familial and sporadic forms of Alzheimer's disease. This discovery might contribute to the search for other primary pathogenic mechanisms, which link perturbed lipid bilayer structures and protein processing and transport in the neuronal Golgi compartment and neurodegeneration and cognitive deficits.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Stoffel, Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED Jenke, Britta UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt-Soltau, Inga UNSPECIFIED UNSPECIFIED UNSPECIFIED Binczek, Erika UNSPECIFIED UNSPECIFIED UNSPECIFIED Brodesser, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Hammels, Ina UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-186705
DOI:	10.1038/s41419-018-0560-7
Journal or Publication Title:	Cell Death Dis.
Volume:	9
Date:	2018
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-4889
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FAMILIAL ALZHEIMERS-DISEASE; NIEMANN-PICK-DISEASE; ACID SPHINGOMYELINASE; NEUTRAL SPHINGOMYELINASE; APOLIPOPROTEIN-E; STORAGE DISEASE; TRANSGENIC MICE; GROWTH-HORMONE; TYPE-4 ALLELE; A-BETA Multiple languages Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18670