Mitochondria and NDD

 Growing evidence, including our results, indicates that abnormalities in mitochondrial function, motility and biogenesis contribute to the pathogenesis of syndromes affecting the developing brain. Our objective is to understand how mitochondrial dysfunction causes brain injury aimed at designing targeted therapeutic and preventive strategies. For this purpose we choose to study the cerebellum since accruing data suggests that it is involved in brain development and cognitive processes in addition to its role in motor functions. Three relevant mouse models are currently studied to establish the link between mitochondrial homeostasis and cerebellar alterations:

1. The Harlequin mouse (Hq), a genuine model of mitochondrial pathology due to the 80-90% reduction of AIF expression in brain tissues, which leads to retinal degeneration, optic atrophy and cerebellar ataxia;
2. The Plp1 dysmyelinating mice, 2 models of X-linked disorders of myelin formation are under study: (a) one reflecting the severe form of Pelizaeus-Merzbacher disease (PMD), due to Plp1 gene duplications which is characterized by predominant cerebellar signs and progressive cerebellar atrophy; (b) a second one mimicking the milder spastic paraplegia type 2 (SPG2) form, related to Plp1 null mutations, which includes learning difficulties and a progressive cerebello-spastic gait related to myelin instability;
3. The Fmr1 knockout mouse, a relevant model of Fragile-X syndrome, the most common known monogenic cause of Autism Spectrum Disorders, which correspond to a group of NDDs;

  The neuroglobin (NGB), a mitochondrial protein known as a powerful neuroprotectant, effectively protects against optic neuropathy in Hq mice by its ability to sustain mitochondrial function. Hence, we will develop a gene therapy strategy with AAV2-NGB vectors to target cerebellar cells in Hq, Plp1 overexpressing/knockout and Fmr1 mice. We intend to establish whether the treatment is effective in: (a) preventing cell loss; (b) inducing the reconstruction of neuronal circuits; (c) reducing gliosis/inflammation; (d) reestablishing the synthesis of myelin; (e) improve the ataxic behavior.

  We are expecting that the data generated will provide valuable insight into: (a) the molecular networks controlling mitochondrial homeostasis in the cerebellum; and (b) the involvement of organelle robustness in the proliferation, maturation and maintenance of neuronal and glial cells. Lastly, if NGB-mediated gene therapy is effective in preventing cerebellar injury in the mouse models studied, the essential role of mitochondrial bioenergetics in ensuring the functional integrity of the brain will be reinforced. Therefore, we can consider setting up clinical trials for a wide range of neurological diseases that are currently incurable and severely disabling.