Matthias Fassler

Spenden & Helfen

Curriculum vitae

Name Matthias Fassler
Place of birth Jena
Date of birth 28/10/1980
   
since 2005

PhD student at the Leibniz Institute for Age Research - Fritz Lipmann Institute, JenaResearch group: “Membrane Trafficking of Proteins involved in Alzheimer’s Disease”PhD thesis: “Understanding the role of Rer1 in the assembly of the g-secretase complex”.

2002/2003 Teaching assistant, FSU Jena
2002 Student research assistant, FSU JenaPeptide synthesis of artificial ligands of SH2 domains
2002-2005 Study of Biochemistry and Molecular Biology at the Friedrich Schiller University Jena, GermanyElective intensive course: Molecular medicineGraduation as Diplom-BiochemikerGrade: 1.3 (A-)Diploma thesis: “Studies on the molecular interaction of recombinant scorpion a-toxins with voltage sensors of sodium channels”
 
1994-1999 Grammar school “Carl Zeiss” for mathematically, technically, scientifically gifted childrenAbitur grade (final secondary school examinations): 1.0 (A)
 

Thesis abstract

Alzheimer’s disease (AD) is the most frequent form of dementia found in the elderly. The Aβ peptides that are the principal component of the amyloid plaques in the brains of AD patients are released to the extracellular space by the activity of g-secretase. The g-secretase is a multimeric, high-molecular-weight complex composed of presenilin (PS), nicastrin, anterior pharynx-defective phenotype 1 (Aph1) and PS enhancer 2 (Pen2). In previous work a quality control mechanism for g-secretase assembly was suggested that is based on retention signals, which keep unassembled subunits and assembly intermediates in the endoplasmic reticulum (ER). These signals become inactivated in the properly assembled complex and the g-secretase is transported to the plasma membrane and the endosomes where it is active. It was the aim of the present study to provide evidence for the proposed quality control hypothesis for g-secretase assembly. Read more

 

Project description

Summary PhD thesis: “Understanding the role of Rer1 in the assembly of the g-secretase complex”

g-secretase is a high molecular weight complex composed of Presenilin (PS), Nicastrin, Aph1 and Pen2. The assembled g-secretase shows pro- tease activity and cleaves several substrates like the amyloid precursor protein (APP) within their transmembrane domain. Thus, g- secretase mediates the final step in the production of the amyloid b-peptide, the principal component of the amyloid plaques in the brains of Alzhei- mer´s disease patients.

The g-secretase complex assembles in the endoplasmic reticulum (ER) and is exported to its sites of activity. A quality control system ensures that only fully assembled g-secretase leaves the ER. We hypothesize, that this quality control mechanism is based on ER-retention/retrieval signals on every g-secretase subunit, which keep the unassembled sub- units in the ER. Upon assembly these signals are supposed to be mas- ked and the subunits are no longer substrate of proteins that facilitate the retention/retrieval.

We previously identified ER- retention/retrieval signals in PS1 and Pen2, both located in transmembrane domains. We also identified a protein, Rer1, which mediates the retention/retrieval of Pen2 via transmem- brane interactions. Thus, we suppose that Rer1 might in- fluence the assembly of g-secretase via the Pen2 subunit.

In the proposed project we want to elucidate the molecular mecha- nisms of g-secretase complex assembly and analyze the role of Rer1 in this process. A siRNA screen to find interaction partners for transmembrane-based retention will be performed. To this end, we will utilize reporter constructs, which undergo Rer1 mediated ER- retention/retrieval as a sensor for the integrity of the Rer1-based quality control mechanism. Cells stably expressing the reporter constructs will be reversely transfected with a siRNA library. Subsequently, the localization of the reporter con- structs will be analyzed using high content microscopy. Additionally, we will screen for direct interaction partners of Rer1 using a yeast 2-hybrid screen based on a human brain cDNA library. It is likely, that we will find proteins in the screens that affect the described quality control mechanism for g-secretase assembly. These proteins will be analyzed further to determine their exact role in the complex assembly of g-secretase.