Elena Rugarli - C 13

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. Our group has a long-standing interest in defining the pathogenic pathways implicated in HSP, and has developed several mouse models for the disease. A big challenge 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.

Mutations in SPG7 are responsible for most cases of autosomal recessive HSP and of mitochondrial disease in adults. SPG7-linked HSP is the prototype of the link between aberrant mitochondrial quality control and axonopathy. We have a long-standing interest in this form of HSP, since our development of Spg7-deficient mice, the first mouse model for HSP (Ferreirinha et al., 2004). Spg7^-/- mice recapitulate the human axonopathy and have been instrumental to demonstrate the exquisite dysfunction of mitochondria in distal regions of spinal axons. SPG7 forms together with the homologous AFG3L2 a functional hetero-oligomeric m-AAA protease in the inner mitochondrial membrane. We have investigated the redundancy between Spg7 and Afg3l2 (Martinelli et al., 2009), which is implicated in spinocerebellar ataxia type 28. Moreover, we have contributed to a molecular understanding of the function of the m-AAA protease in healthy mitochondria, including its role in mitochondrial translation, and mitochondrial dynamics and trafficking (Almajan et al., 2012; Ehses et al., 2009; Kondadi et al., 2014).

The most common autosomal dominant form of HSP is due to mutations in SPG4 (or SPAST), encoding spastin. We demonstrated that spastin is a microtubule-severing protein (Errico et al., 2002), which localizes to areas characterized by highly dynamic microtubules.  Moreover, we identified a neuronal-enriched isoform of spastin targeted to the endoplasmic reticulum with a specific role in lipid droplet metabolism (Papadopoulos et al., 2015). These data have contributed to the hypothesis that an impairment of microtubule-severing coupled to the remodeling of the ER membrane where lipid droplets are formed causes axonal degeneration in HSP.

In this project we aim to investigate whether degeneration of CSMN axons in HSP is caused by unifying neuronal dysfunctional pathways or by the local activation of axonal death cascades. To this purpose, we will initially focus on the two most common forms of autosomal dominant and recessive HSP, caused by mutations in the SPG4 and SPG7 genes, respectively.

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.

1. 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. doi.org: 10.1002/glia.23626.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.