Skip to main content

Molecular mechanism(s) of neurodegeneration in Niemann-Pick type C disease

Principal investigator

Category
Projekti Hrvatske zaklade za znanost
Start date
Jun 1st 2017
End date
May 31st 2021
Status
Done

Laboratory for Neurodegenerative Disease Research

Molecular mechanism(s) of neurodegeneration in  Niemann-Pick type C disease

Niemann-Pick type C disease (NPC) is a rare inherited lysosomal storage disorder characterized by lysosomal cholesterol accumulation leading to progressive neurodegeneration. It is intriguing that this rare disease (caused by mutations in NPC1or NPC2genes) shows several key features of a complex Alzheimer's disease (AD) including accumulation of amyloid-β (Aβ) peptides and hyperphosphorylation of tau.

Slide3

However, these two neurodegenerative disorders show different regional vulnerabilities; while hippocampus is the most affected region in AD and is spared in NPC disease, the cerebellum is spared in AD but is primarily affected in NPC resulting in extensive loss of Purkinje cells. In this project we will use the knowledge gained through extensive research on the most common neurodegenerative disease AD to elucidate molecular mechanism(s) of neurodegeneration in a rare disorder NPC. We have previously reported that increased levels of Aβ in NPC are due to enhanced β-secretase (BACE1) processing of β-amyloid precursor protein (APP).

Slide2

In addition to APP, novel BACE1 substrates were recently identified making BACE1 a major sheddase in the nervous system. Based on these findings, in this project we will elucidate the role of BACE1 in the pathogenesis of NPC and whether BACE1 may represent a novel target for treating/ameliorating NPC disease. We will analyze BACE1-proteolysis and distribution of APP and the two recently identified top BACE1 substrates in hippocampus and cerebellum of NPC1- and wt-mice. Primary hippocampal and cerebellar Purkinje neuronal cultures will be used to dissect the mechanism(s) of the BACE1-mediated effect on pathological features of NPC. Also, we will develop anex vivo model of NPC disease using hippocampal and cerebellar organotypic brain slices and will monitor whether BACE1-inhibition may prevent/ameliorate any of the NPC pathological features. Lastly, we will genetically deplete BACE1 in NPC1-mice to validate our findingsin vivo.

Slide5

These studies may indicate a role of BACE1 in NPC pathogenesis and the potential of targeting BACE1 as an alternative approach for treating this devastating disease.

Other associates

Kristina Dominko, mag.biol.mol., researcher

Ana Rastija, mag.biol.mol., PhD student

Lea Vidatić, mag.biol.exp., researcher

  

DZNE - Munich, Germany

  

Sabina Tahirović https://www.dzne.de/en/sites/munich/research-groups/tahirovic.html

Alessio Colombo 

Stefan Lichtenthaler https://www.dzne.de/en/sites/munich/research-groups/lichtenthaler.html

This site uses cookies.

Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and can only be disabled by changing your browser preferences.