Master Thesis: Non-coding RNA in neurodegenerative diseases

Advertising institute: IAS-5 – Computational Biomedicine
Reference number: D131/2015, Physics, Chemistry, Biology or related fields

The section ‘Structural Neuroinformatics’ INM-9/IAS-5 Computational Biomedicine at Forschungszentrum Jülich offers a dynamic and international work environment. Our lab develops and uses multi-scale simulation and structural bioinformatics tools to gain insights on important molecular events in signaling pathways. Collaboration with experimental labs around the world and industry is an important pillar of our work.

Brain derived neurotrophic factor (BDNF) is the most abundant and widespread expressed neurotrophin in the human brain. It has a central role in neuronal development and physiology and more recently it has also emerged as a key player of plasticity-related processes occurring in adult brain, including memory and learning. BDNF is initially synthesized in the endoplasmic reticulum as a precursor protein, pre-pro-BDNF, which is then converted into pro-BDNF by removal of the signal peptide. The molecule is further processed into the mature form, mature BDNF.

Notably pro- and mature BDNF activate two distinct receptors producing diametrically opposing effects on cell survival: proper BDNF signaling requires the binary actions of both the forms (pro- versus mature).

Disruption of BDNF signaling in the brain has been linked in recent years to a range of psychiatric and neurological disorders. In this respect, a functional single nucleotide polymorphism (SNP) at nucleotide 196 in the BDNF gene, termed the rs6265 polymorphism, is associated with memory impairment in humans and variety of psychiatric and neurological disorders. The rs6265 polymorphism results in an amino acid residue shift from valine (Val) to methionine (Met) at codon 66 (nucleotide 196) in the 5′ pro-region of BDNF. The polymorphism does not lead to sequence changes of the mature BDNF protein itself, but affects the trafficking of pro-BDNF mRNA. Specifically this effect was found to be due to a reduced affinity of the rs6265 BDNF mRNA toward the translin/trax-complex. This complex is also known as C3PO and regulates mRNA stability and translation at synapses. Thus, abnormal interactions of an mRNA with Translin may have profound effects on its trafficking, stability and translation.

A better understanding of the structural determinants of such complex could help not only to increase our understanding of pathophysiology across psychiatric disorders, but also open new perspectives for pharmacological treatment strategies, including the developing of new agents for personalized treatments that maximize treatment effects and limits side effects.

The general aims of this project are:
(i) modeling of WT and mutated BDNF mRNA;
(ii) identification of the molecular determinants for BDNF mRNA and Translin/Trax complex

We offer an excellent scientific infrastructure and technical assistance.

The candidate should be familiar with the UNIX-like environment.

Please send your application to:
Forschungszentrum Jülich GmbH
INM-9/IAS-5 Computational Biomedicine
Jun.-Prof. Dr. Giulia Rossetti

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