Mitochondria and Axonal degeneration in DOA: a story of shape and function.

P.I. P. Belenguer, MC Miquel

Distal axonal and synaptic dysfunctions precede, and might even be causative for neuronal loss in neurodegenerative diseases. There is growing evidence that mitochondria, by their function, repartition and motility, play a crucial role in the retrograde propagation of the degenerative signal. DOA is characterized by the progressive loss of retinal ganglionic cells (RGC), which axons form the optic nerve. This neurodegenerative pathology is due to mutations in the gene encoding OPA1, leading to mitochondrial dysfunctions and misdistribution along neurites.

To determine why RGC are especially sensitive to an OPA1-depleted environment and to better prevent RGC loss in DOA, we focus in this project on the properties of RGC axons using retinal explants of DOA mice and innovative culture devices based on microfluidics, that enable axonal growth through micro-channels of different shapes.

Former PI/ Marion Szelechowski (post-doct)

Collaborators: Jean-Michel Peyrin (Institut de Biologie Paris Seine, CNRS UMR 8246/INSERM U 1130, Paris), Alexandra Rebsam (Institut de la Vision, Paris)

Publications:

• Lassus B, Magnifico S, Pignon S, Belenguer P, Miquel MC & Peyrin JM (2016) Alterations of mitochondrial dynamics allow retrograde propagation of locally initiated axonal insults, Scientific Report, 8;6: 32777.
• Magnifico S, Saias L, Deleglise B, Duplus E, Kilinc D, Miquel MC, Viovy JL, Brugg B, Peyrin JM. (2013) NAD+ acts on mitochondrial SirT3 to prevent axonal caspase activation and axonal degeneration. FASEB J., 27(12) 4712-22.
• Bertholet AM, Millet A, Guillermin O, Daloyau M., Davezac N., Miquel MC, Belenguer P. (2013) OPA1 loss of function affects in vitro neuronal maturation BRAIN, 136:1518-33.

Funding