Prof. Dr. Elena Rugarli

Research Area: Disruptions in Protein Metabolism Cause Aging-Associated Diseases

Website:  http://rugarli.cecad-labs.uni-koeln.de/

1. Research Background:

We aim to understand the mechanisms underlying axonal degeneration, a chronic process that plays an important role in several neurodegenerative diseases. We study the function of several proteins involved in hereditary spastic paraplegia, a disease characterized by degeneration of the corticospinal axons. Ultimately, we aim to a better understanding of the pathophysiology of this disease, and to unravel possible therapeutic avenues.

2. Research questions addresses by the group:

  1. We study the functions of genes involved in hereditary spastic paraplegia (HSP), an adult-onset genetic disorder, characterized by progressive weakness and spasticity of the lower limbs and due to the retrograde degeneration of the longest axons of the central nervous system, those composing the corticospinal tracts. We combine cell biological approaches and the development of animal models to study the functions of different HSP genes involved in mitochondrial quality control, microtubule dynamics, and lipid metabolism. Our aim is to shed light on the pathogenesis of HSP and identify common disrupted pathways amenable of therapy.
  2. Neuronal survival critically depends on the integrity and functionality of mitochondria. A hierarchical system of control mechanisms protects mitochondria against stress, monitors mitochondrial damage and ensures the selective removal of dysfunctional mitochondrial proteins or organelles. We study post-transcriptional mechanisms of regulation of mitochondrial function and their role in physiology and disease.

3. Possible projects:

ERLIN1 and ERLIN2 are homologous proteins of about 40 kDa that assemble in hetero-oligomeric or homo-oligomeric high-molecular weight complexes. ERLINs belong to the SPFH family of proteins, which have been proposed to organize membrane microdomains with distinct lipid and protein composition.  Loss-of-function mutations in ERLIN1 and ERLIN2 genes have been found in patients affected by hereditary spastic paraplegia (HSP), a genetically heterogeneous neurological disease characterized by progressive degeneration of central motor axons. The ERLINs localize to the endoplasmic reticulum (ER), bind cholesterol, and promote ER-associated degradation of specific substrates, however how lack of ERLINs leads to HSP remains enigmatic.

4. Applied Methods and model organisms:

In this project, we aim to investigate the molecular mechanisms by which the ERLIN complexes regulate ER morphogenesis by using a combination of candidate molecule approaches and of unbiased proteomics and lipidomics strategies. We will define the protein and lipid scaffolding functions of ERLINs in the ER . Finally, to investigate the role of the ERLIN complexes in vivo in the nervous system and assess if altered pathways identified in vitro are relevant for the degeneration of long motor axons, we will develop and characterize Erlin1-deficient, Erlin2-deficient, and double Erlin1/2-deficient mice.

5. Desirable skills and qualifications:

The successful candidate must have a degree (master/diploma) in science (e.g. biology, biochemistry, chemistry or biotechnology) and a strong research interest in neuroscience and cell biology. Previous experience in cell biology or mouse genetics is an advantage but not a pre-requisite. Fluency in written and spoken English is required.

6. References:

  • Papadopoulos C, Orso G, Mancuso G, Herholz M, Gumeni S, Tadepalle N, Jungst C, Tzschichholz A, Schauss A, Honing S, Trifunovic A, Daga A, and Rugarli EI (2015). Spastin binds to lipid droplets and affects lipid metabolism. PLoS Genet 11, e1005149.
  • Kondadi A.K., Wang S., Montagner S., Kladt N., Korwitz A., Martinelli P., Herholz D., Baker M.J., Schauss A.C., Langer T., Rugarli E.I. (2014) Loss of the m-AAA protease subunit AFG3L2 causes mitochondrial transport defects and tau hyperphosphorylation. EMBO J. 33(9):1011-26
  • Almajan  E.R., Richter R., Paeger L., Martinelli P., Barth E., Decker T., Larsson N-G, Kloppenburg P., Langer T.,  Rugarli E.I. (2012) AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival. J. Clin. Invest; 122:4048-58. doi: 10.1172/JCI64604.