Center for Molecular Medicine Cologne

Rugarli, Elena - C 13

Mapping hereditary spastic paraplegia: towards common pathogenic and novel rescue pathways


Hereditary spastic paraplegia (HSP) is an inherited progressive neurological condition characterized by weakness and spasticity of the lower limbs, owing to the selective degeneration of axons of corticospinal motoneurons (CSMNs). No therapy, besides symptomatic treatment, is currently available for HSP patients, who experience progressive difficulties in ambulation, ultimately leading to wheelchair confinement. CSMNs are the most polarized central neurons, with axons that can reach the remarkable length of 1 m in humans. During life, these axons depend on the continuous trafficking of lipids, proteins, and organelles from the neuronal soma. Pathogenic pathways implicated in HSP include: mitochondrial dysfunction; disturbances of the cytoskeleton and axonal trafficking; alterations of the shaping of the endoplasmic reticulum (ER); defects in autophagy and lysosomal function; and aberrant lipid metabolism. Despite considerable progress in isolating novel HSP genes and studying their function, key questions remain:

  1. Is there a central unifying pathogenic mechanism in different HSP forms?
  2. What is the role of soma-derived versus axon-localized perturbed pathways in HSP pathogenesis?
  3. How do corticospinal axons die?

Answering these questions is necessary to meet the challenge to identify druggable convergent targets in seemingly heterogenous forms of HSP.

Figure 1

Our Aims

In this project we investigate whether degeneration of CSMN axons in HSP is caused by unifying neuronal dysfunctional pathways or local activation of axonal death cascades. To this end, we will perform high-throughput unbiased analyses across representative forms of HSP, using integrated transcriptomics, proteomics, lipidomics and metabolomics in established mouse models. Analyses will be performed ex vivo on the spinal cord and other relevant tissues and in vitro on neuronal soma and axons isolated by means of microfluidic chambers. Identified pathways will be further explored in cellular models and probed for cross-species conservation on HSP patients’ biomaterial. Our ultimate goal is to identify and test convergent druggable targets to prevent or block disease progression in genetically different forms of HSP.

Our study will allow:

  1. to identify shared early-onset pathogenic pathways among different forms of HSP
  2. to discover if the mechanism of axonal death is conserved;
  3. to instruct drug-repurposing strategies as novel therapeutic approaches.

Publications listed here and marked with an asterisk resulted in affiliation with the CMMC.

  • Murru S, Hess S, Barth E, Almajan ER, Schatton D, Hermans S, Brodesser S, Langer T, Kloppenburg P, and Rugarli EI. (2019) Astrocyte-specific deletion of the mitochondrial m-AAA protease reveals glial contribution to neurodegeneration. Glia. 2019, 1-16. 10.1002/glia.23626.
  • Wang S, Jacquemyn J, Murru S, Martinelli P, Barth E, Langer T, Niessen CM, and Rugarli EI. (2016) The mitochondrial 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.
  • Martinelli P, La Mattina V, Bernacchia A, Magnoni R, Cerri F, Cox G, Quattrini A, Casari G, and Rugarli EI. (2009) Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration. Hum Mol Genet. 18, 2001-2013.
  • Ehses S, Raschke I, Mancuso G, Bernacchia A, Geimer S, Tondera D, Martinou JC, Westermann B, Rugarli EI*, and Langer T*. (2009) Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1. J Cell Biol. 187, 1023-36.
  • Pirozzi M, Quattrini A, Andolfi G, Dina G, Malaguti MC, Auricchio A, and Rugarli EI. (2006) Intramuscular viral delivery of paraplegin rescues peripheral axonopathy in a model of hereditary spastic paraplegia. J Clin Invest. 116, 202-208.
  • Ferreirinha F, Quattrini A, Pirozzi M, Valsecchi V, Dina G, Broccoli V, Auricchio A, Piemonte F, Tozzi G, Gaeta L, Casari G, Ballabio A, and Rugarli EI. (2004) Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport. J Clin Invest. 113, 231-42.
  • Errico A, Ballabio A, and Rugarli EI. (2002) Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. Hum Mol Genet. 11, 153-163.
  • Schatton D, Di Pietro G, Szczepanowska K, Veronese M, Marx MC, Braunohler K, Barth E, Muller S, Giavalisco P, Langer T, Trifunovic A, and Rugarli EI (2022). CLUH controls astrin-1 expression to couple mitochondrial metabolism to cell cycle progression. Elife11. doi:10.7554/eLife.74552.
  • Wani GA, Sprenger HG, Ndoci K, Chandragiri S, Acton RJ, Schatton D, Kochan SMV, Sakthivelu V, Jevtic M, Seeger JM, Muller S, Giavalisco P, Rugarli EI,Motori E, Langer T, and Bergami M (2022). Metabolic control of adult neural stem cell self-renewal by the mitochondrial protease YME1L. Cell Rep38, 110370. doi:10.1016/j.celrep.2022.110370.
  • Tadepalle N, and Rugarli EI (2021). Lipid Droplets in the Pathogenesis of Hereditary Spastic Paraplegia. Front Mol Biosci8, 673977. doi:10.3389/fmolb.2021.673977.
  • Pla-Martin D, Schatton D, Wiederstein JL, Marx MC, Khiati S, Kruger M, and Rugarli EI (2020). CLUH granules coordinate translation of mitochondrial proteins with mTORC1 signaling and mitophagy. EMBO J 39, e102731.
Prof. Dr. Elena Rugarli CMMC Cologne
Prof. Dr. Elena Rugarli

CECAD Cologne & Institute for Genetics

CMMC - PI - C 13

+49 221 478 84244

+49 221 478 97902

CECAD Cologne & Institute for Genetics

Joseph-Stelzmann-Str. 26

50931 Cologne

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Curriculum Vitae (CV)

Publications - Elena Rugarli

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