The m-AAA protease and the regulation of mitochondrial ribosome assembly
Axon degeneration is a process that plays an important role in many neurodegenerative diseases. Premature axon death occurs preferentially in long neurons, such as the corticospinal tract that runs from the cerebral cortex into the spinal cord with axons up to one meter long. Under the leadership of Prof. Elena Rugarli, the CECAD working group is exploring hereditary spastic paraplegia (HSP), a group of rare genetic disorders causing the degeneration of axons of the corticospinal tract. Patients who suffer from HSP experience progressive spasticity and weakness in their lower limbs. In the later stages of the disease, patients may even be confined to a wheelchair.
Mutations in many genes are associated with the pathogenesis of HSP. Prof. Rugarli’s team is working on exploring the functions of several of these genes to identify the mechanisms behind axo-nal degeneration. The team’s scientists are mainly focusing on two HSP genes: SPG7 and SPAST. SPG7 encodes for paraplegin, a subunit of the mitochondrial m-AAA protease. Remarkably, paraplegin assembles with AFG3L2, which is mutated in another neurodegenerative condition, spinocerebellar ataxia SCA28. Thus, the group is using in vivo models to investigate the role of the mitochondrial m-AAA protease in neurodegeneration. SPAST encodes for spastin, a protein which breaks microtubules along their length. Another goal of the group is to understand a possible role of spastin and other HSP genes in lipid metabolism, an approach that could hold promises to find novel therapeutic strategies for HSP.
Gao, J., Schatton, D., Martinelli, P., Hansen, H., Pla-Martin, D., Barth, E., Becker, C., Altmueller, J., Frommolt, P., Sardiello, M., and Rugarli, E.I. (2014). CLUH regulates mitochondrial biogenesis by binding mRNAs of nuclear-encoded mitochondrial proteins.J. Cell Biol. 207, 213-223.
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. 2014 May 2;33(9):1011-26. doi: 10.1002/embj.201387009. Epub 2014 Mar 28.
Almajan ER, Richter R, Paeger L, Martinelli P, Barth E, Decker T, Larsson NG, Kloppenburg P, Langer T, Rugarli EI. (2012) AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival. J. Clin. Invest; 122:4048-58. doi: 10.1172/JCI64604.