This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie COFUND grant agreement No 665735.

Bio4Med Research Projects:


<<< back to list

10: Bio4Med - The role of Amyloid precursor protein (APP) differential processing in neuromuscular junction development and in the pathology of inclusion body myositis

Supervisor:
dr Tomasz Proszynski
Foreign partner:
Prof. Lawrence Rajendran Laboratory, the University of Zurich, Switzerland
WWW
http://www.nencki.gov.pl/pracownia-synaptogenezy
Background:
Like synapses in the brain, NMJs undergo intense synaptic remodeling during postnatal development. Although abnormalities in the NMJ development are often observed in various neuromuscular disorders, the molecular machinery responsible for the plasticity of these synapses is poorly understood. Recent studies demonstrated that APP, the substrate for Aβ production, is also localized to the NMJ postsynaptic machinery, where it plays a pivotal role in the formation and maturation of these synapses. Interestingly, muscle-specific expression of the extracellular domain of APP in APP knockout mice was sufficient to rescue NMJ formation, but not defects in its postnatal maturation. NMJs in these mice were often fragmented, which is usually a hallmark of premature aging of the NMJ. These results suggest that various APP domains have distinct functions in the stabilization and remodeling of NMJs. Previous studies showed that substantial amounts of Aβ are produced in muscles and that this peptide may regulate synaptic transmission. Additionally, Aβ aggregates, together with β-secretase (BACE), accumulate in muscle tissue in the form of inclusion bodies that cause inclusion-body myositis (IBM), the most common progressive muscle disease in the elderly considered to be a muscle equivalent of Alzheimer’s. Although both full-length APP and some of its cleaved domains have clearly documented functions at the NMJ and in muscle pathology, little is known about APP processing in muscles.
Aim:
We will investigate the role of different APP processing enzymes in the formation and maturation of the NMJ as well as in the pathology of inclusion-body myositis.
Requirements:
Ideal candidate should have experience in Cell culture and working with living animals Excellent interpersonal and communication skills Strong motivation to work in science Neatness in work habits, attention to detail, and good organizational skills Ability to communicate fluently in English General experience in laboratory work Candidates must not have resided or carried out their main activity (work, studies, etc.) in Poland for more than 12 months in the past 3 years.