Naslov
Subcellular localization of BACE1 substrates SEZ6 and SEZ6L is altered in primary neurons of Niemann-Pick type C murine model

Autori
Vidatić, Lea ; Dominko, Kristina ; Rastija, Ana ; Pigoni, Martina ; Colombo, Alessio, Gunnersen, Jenny M. ; Tahirović, Sabina ; Lichtenthaler, Stefan F. ; Hećimović, Silva

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, neobjavljeni rad, znanstveni

Skup
The 14th International Conference on Alzheimer's & Parkinson's Diseases

Mjesto i datum
Lisabon, Portugal, 26.03.2019. - 31.03.2019

Vrsta sudjelovanja
Poster

Vrsta recenzije
Nije recenziran

Ključne riječi
BACE1 substrates ; cholesterol ; NPC1 ; primary neurons ; Seizure 6 related proteins

Sažetak
A rare, inherited lysosomal storage disorder Niemann-Pick type C (NPC) shares several similarities with Alzheimer's disease (AD). In NPC1-/- mouse brains, we have recently reported enhanced processing of β-amyloid precursor protein (APP), seizure protein 6 (SEZ6) and seizure 6-like protein (SEZ6L) by β-secretase (BACE1), a key enzyme in the pathogenesis of AD. In this work we tested whether increased BACE1-proteolysis of Sez6 and Sez6L involves their altered trafficking within the endolysosomal pathway, as we previously observed for APP. We analysed the subcellular localization of BACE1, Sez6 and Sez6L in primary cortical neurons isolated from NPC1-/- (NPC1) and NPC1+/+ (wt) mice. Neurons were isolated from postnatal day 0 pups, grown in vitro for 14 days, immunostained and analysed by confocal microscopy. NPC1 primary mouse cortical neurons showed accumulation of free cholesterol in the cell body and enlarged lysosomes which are characteristic features of NPC disease. More puncta of early and recycling endosomal markers were detected in the processes of NPC1 compared to wt cortical neurons. Also, NPC1 cortical neurons showed enhanced punctuate colocalization of both Sez6 and Sez6L with transferrin receptor (TfR). These results demonstrate that cholesterol accumulation, upon NPC1-dysfunction, causes altered trafficking of BACE1 substrates Sez6 and Sez6L within the endolysosomal pathway, in addition to APP. Altered function of BACE1 and its substrates may play a role in NPC disease pathogenesis.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

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