Rugarli, Elena I - C 10
The Role of the Integrated Stress Response and of Paraplegin-specific Substrates in Neurodegeneration Caused by Mutations in SPG7
Prof. Dr. Elena I Rugarli
Institute for Genetics | CECAD Research Center
CMMC - PI - C 10
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Institute for Genetics | CECAD Research Center
Joseph-Stelzmann-Str. 26
50931 Cologne
Introduction
Mutations in SPG7 are among the most common causes of recessive hereditary spastic paraplegia (HSP), a progressive neurodegenerative condition characterized by weakness and spasticity of the lower limbs, owing to the dying-back of the long corticospinal axons. Currently, there is no treatment that successfully blocks the progression of the symptoms, and patients become ultimately bound to a wheel-chair. SPG7 encodes for paraplegin, one of two subunits of the mitochondrial matrix (m)-AAA protease. This hexameric complex is embedded in the inner mitochondrial membrane and exerts key quality control and regulatory functions in the mitochondria. Substrates of the m-AAA protease range from components of the respiratory chain and the mitochondrial calcium uniporter to mitoribosomal subunits.
As often the case in mitochondrial and neurodegenerative diseases, it is unclear why mutations in a ubiquitously expressed protein leads to the demise of very specific axonal tracts. Possible contributing factors are the extreme polarization of the affected neurons, the existence of paraplegin-specific substrates expressed in these neurons, and the activation in neurons of maladaptive stress responses following mitochondrial dysfunction. Here, we aim to investigate the role of the integrated stress response (ISR) and of potential paraplegin-specific substrates in determining the progression and tissue specificity of the pathological process in SPG7 deficiency, using murine and cellular models. Answering these questions could reveal novel therapeutic avenues for the human disease.
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Clinical Relevance
Mutations in SPG7 are among the most common cause of recessive HSP. In this proposal, our goals are: (1) To restrict the mitochondrial processes affected in HSP patients and customize therapeutic strategies, by identifying SPG7-specific substrates; (2) To assess the pathogenic role of the ISR in affected neurons. Since compounds that counteract or prolong the ISR are available, our research can reveal novel therapeutic avenues for future exploration.
Approach
- Genetics interactions in vivo
- Cellular model systems
- Immunoprecipitation experiments
Selected Publications
- Zaninello M, Schlegel T, Nolte H, Pirzada M, Savino E, Barth E, Klein I, Wüstenberg H, Uddin T, Wolff L, Wirth B, Lehmann HC, Cioni JM, Langer T, Rugarli EI (2024). CLUH maintains functional mitochondria and translation in motoneuronal axons and prevents peripheral neuropathy. Sci Adv. 10(22):eadn2050. DOI: 10.1126/sciadv.adn2050
- 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. PMID: 37086482
- Murru S, Hess S, Barth E, Almajan ER, Schatton D, Hermans S, Brodesser S, Langer T, Kloppenburg P, Rugarli EI (2019). Astrocyte-specific deletion of the mitochondrial m-AAA protease reveals glial contribution to neurodegeneration. Glia. 2019, 1-16. DOI: 10.1002/glia.23626
- Wang S, Jacquemyn J, Murru S, Martinelli P, Barth E, Langer T, Niessen CM, Rugarli EI (2016). The mitochondrial m-AAA protease prevents demyelination and hair greying. PLoS Genet. 12, e1006463. DOI: 10.1371/journal.pgen.1006463
Lab Website
For more research information, please check Rugarli Lab.
Affiliations
Publications generated during 1/2026-12/2028 with CMMC affiliations
2026
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