Prof. Dr. Elena Rugarli

Research Area: Mitochondrial Dysfunction and Neurodegeneration

Branches: Biomedical ResearchCell BiologyNeurobiology

Website: Rugarli Lab

1. Research Background:

Axonal degeneration is a chronic process that plays an important role in several neurodegenerative diseases. We study the function of several proteins involved in hereditary spastic paraplegia (HSP), a disease characterized by progressive degeneration of the distal corticospinal axons. Ultimately, we aim to a better understanding of the pathophysiology of this disease, and to unravel possible therapeutic avenues. In addition, we unravel basic biological mechanisms that maintain the quality of mitochondria in neurons, including intra-organellar proteases and post-transcriptional regulators of mRNAs encoding mitochondrial proteins.

Our group has a long-standing interest in defining the pathogenic pathways implicated in HSP. We have been studying the function of spastin, the protein most commonly implicated in HSP, and the role of the mitochondrial m-AAA protease, which is dysfunctional in both HSP and spinocerebellar ataxia. A bigchallenge in the field is to pinpoint pathogenic commonalities among HSP forms of different genetic origin, in order to identify shared therapeutic approaches for HSP patients. Interestingly, as new HSP genes have been cloned and their protein products characterized, defects in the morphogenesis of tubular endoplasmic reticulum (ER) have stood out as a primary pathogenic pathway in HSP.

2. Research questions addressed by the group:

We are interested in answering the following questions:

  • Which cellular pathways are involved in maintaining the viability of long motor axons?
  • How is the quality and function of mitochondria regulated, especially in neurons and along axons?

To address these questions, we study the basic function of genes involved in hereditary spastic paraplegia, a genetic disease characterized by degeneration of the central motor axons.

3. Possible projects:

ERLIN1 and ERLIN2 are homologous proteins of about 40 kDa that assemble in hetero-oligomeric orhomo-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. The ERLINs localize to the endoplasmic reticulum (ER), bind cholesterol, and promote ER- associated degradation of specific substrates. Loss-of-function mutations in ERLIN1 and ERLIN2 genes have been found in patients affected by hereditary spastic paraplegia (HSP), agenetically heterogeneous neurological disease characterized by progressive degeneration of central motor axons. How lack of ERLINs leads to HSP remains enigmatic. As ER membrane organizers, ERLINs are ideally placed in the centre of a network of proteins affecting different aspects of ER function that are dysfunctional in HSP. We hypothesize that ERLINs provide functional scaffolds in the ER membrane that arecrucial for axonal maintenance during life. The project aims to employ already established in vitro and in vivo models of ERLIN deficiency to unravel novel functions of this complex and their relevance in the nervous system.

4. Applied Methods and model organisms:

  • Model organisms: transgenic mice.
  • Methods: Genetics, advanced microscopy, mass spectrometry, molecular biology, systems biology (transcriptomics, proteomics, metabolomics), biochemistry, histochemistry.

5. Desirable skills and qualifications:

We are looking for candidates with a solid background knowledge acquired during master studies (biology, neuroscience, biochemistry, biotechnology), high motivation to be part of a dynamic team, and passion and enthusiasm for science.

6. References:

  • Tadepalle, N. and Rugarli, E.I. (2021). Lipid Droplets in the Pathogenesis of Hereditary Spastic Paraplegia. Front. Mol. Biosci., 10 May 2021. 8:673977. doi: 10.3389/fmolb.2021.673977. eCollection 2021. Review
  • Tadepalle, N., Robers, L. Veronese, M. Zentis, P. , Babatz, F. Brodesser, S. Gruszczyk, A.V., Schauss, A., Hoening, S., and Rugarli, E. I. (2020). Microtubule- dependent and independent roles of spastin in lipid droplet dispersion and biogenesis Life Sci. Alliance 3 (6):e202000715.
  • Murru, S., Hess, S., Barth, E., Almajan, E.R., Schatton, D., Hermans, S., Brodesser, S., Langer, T.,Kloppenburg, P. and Rugarli, E.I. (2019). Astrocyte-specific deletion of the mitochondrial m-AAA protease reveals glial contribution to neurodegeneration. Glia 67(8):1526-1541.
  • Wang S, Jacquemyn J, Murru S, Martinelli P, Barth E, Langer T, Niessen CM, and Rugarli EI. (2016) Themitochondrial m-AAA protease prevents demyelination and hair greying. PLoS         Genet. 12, e1006463. doi:10.1371/journal.pgen.1006463.
  • Papadopoulos C, Orso G, Mancuso G, Herholz M, Gumeni S, Tadepalle N, Jüngst C, Tzschichholz A,Schauss A, Höning S, Trifunovic A, Daga A, and Rugarli EI. (2015) Spastin binds to lipid droplets and affects lipid metabolism. PLoS Genet. 11, e1005149. doi: 10.1371/journal.pgen.1005149.
  • Kondadi AK, Wang S, Montagner S, Kladt N, Korwitz A, Martinelli P, Herholz D, Baker MJ, Schauss AC, Langer T, and Rugarli EI. (2014) Loss of the m-AAA protease subunit AFG3L2 causes mitochondrial transport defects and tau hyperphosphorylation. EMBO J. 33, 1011-26.
  • Almajan ER, Richter R, Paeger L, Martinelli P, Barth E, Decker T, Larsson NG, Kloppenburg P, Langer T, and Rugarli EI. (2012) AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival. J Clin Invest. 122, 4048-58. doi: 10.1172/JCI64604.