Elena I. Rugarli

Institute for Genetics

Mitochondria and Neurodegeneration

In our brain, axons transmit information over long distances, and are susceptible to degenerate during aging and in pathological conditions. We study how axons are preserved during life and how mitochondrial integrity power axonal function.

Research Focus

We are interested in understanding how axons maintain their function during a lifetime. Human axons can reach the length of 1 m, and contain up to 99% of the cytoplasm. Axonal function and survival depend on efficient trafficking mechanisms to deliver proteins, lipids, and cellular organelles, including mitochondria, to their distal regions. Neuronal survival critically depends on the integrity and functionality of mitochondria. We aim to understand which cellular pathways are implicated in axonal degeneration. Moreover, we investigate how the quality and the function of mitochondria is regulated and maintained in axons during life.

The Rugarli group’s research is also dedicated to understanding how the viability of axons in healthy people is maintained over the course of many decades. One approach to tackle this question is to understand the function of genes that contribute to the pathogenesis of genetic diseases characterized by axonal degeneration (for instance heredity spastic paraplegia, HSP).  The researchers’ ultimate vision is to identify common signal cascades triggered in the axons that would allow for interventions. A second approach is to elucidate processes that maintain the functionality of distal axonal organelles, such as the endoplasmic reticulum and the mitochondria in axons. Decoding the process of axonal degeneration is not only important for a better understanding of HSP. The results could also translate to other aging-associated neurodegenerative diseases such as Parkinson’s or Alzheimer’s.

Axons are like long and narrow roads connecting a main factory to outposts located far away. Avoiding traffic accidents and maintaining the efficiency of the outposts is essential during our lifetime. Understanding how this is achieved is at the core of our research.

Our Goals

Our lab has contributed to the understanding of the molecular and cell biological function of several HSP genes, and pinpointed the pathogenic role of defective microtubule-severing, lipid droplet metabolism, and mitochondrial quality control in the degenerative process. In addition, the group is studying a post-translational mechanism to regulate mitochondrial biogenesis, which involves the cytosolic RNA-binding protein CLUH. CLUH binds nuclear-encoded mRNAs for mitochondrial proteins and control their stability and translation. The ultimate goal is to achieve a deeper understanding of the processes that maintain mitochondrial quality in neurons and theor long axonal processes.

Our current aims include:

  • Shed light on the pathogenesis of hereditary spastic paraplegia (HSP), and identify common disrupted pathways amenable to therapy.
    HSP is a genetic disorder, characterized by progressive weakness and spasticity of the lower limbs owing to the retrograde degeneration of the central motor axons, which are responsible for voluntary movements. We investigate the basic function of different HSP genes using cell biology approaches and murine model systems. We are also interested in defining stress cascades activated in axons during the degenerative process.
     
  • Identify mechanisms that maintain the quality of axonal distal mitochondria.
    We investigate the physiological role of intra-mitochondrial proteases that perform quality control of the mitochondrial proteome and regulate the activity of specific mitochondrial proteins. In addition, we are interested in how cytosolic RNA-binding proteins control the fate of mRNAs encoding mitochondrial proteins.

Key Publications


  1. Montoro-Gámez C, Nolte H, Molinié T, Evangelista G, Tröder S, Barth E, Popovic M, Trifunovic A, Zevnik B, Langer T, Rugarli EI (2023). SARM1 deletion delays cerebellar but not spinal cord degeneration in an enhanced mouse model of SPG7 deficiency. Brain 146(10):4117-4131. DOI: 10.1093/brain/awad136.
     
  2. Pla-Martin D, Schatton D, Wiederstein JL, Marx MC, Khiati S, Krüger M, Rugarli EI (2020). CLUH granules coordinate translation of mitochondrial proteins with mTORC1 signaling and mitophagy. EMBO J 39(9):e102731. DOI: 10.15252/embj.2019102731 (Open access).
     
  3. Schatton D, Pla-Martin D, Marx MC, Hansen H, Mourier A, Nemazanyy I, Pessia A, Zentis P, Corona T, Kondylis V, Barth E, Schauss AC, Velagapudi V, Rugarli EI (2017). CLUH regulates mitochondrial metabolism by controlling translation and decay of target mRNAs. J Cell Biol. 216(3): 675-693. DOI: 10.1083/jcb.201607019 (Open access).
     
  4. Kondadi AK, Wang S, Montagner S, Kladt N, Korwitz A, Martinelli P, Herholz D, Baker MJ, Schauss AC, Langer T, Rugarli EI (2014). Loss of the m-AAA protease subunit AFG3L2 causes mitochondrial transport defects and tau hyperphosphorylation. EMBO J 33(9):1011-1026. DOI: 10.1002/embj.201387009 (Open access).
     
  5. Ferreirinha F., QuattriniA., PirozziM., ValsecchiV., DinaG., BroccoliV., AuricchioA., PiemonteF., TozziG., GaetaL., CasariG., BallabioA., Rugarli E.I.Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport, J. Clin. Invest., 113, 231-42, 2004.