Harlequin mice exhibit cognitive impairment, severe loss of Purkinje cells and a compromised bioenergetic status due to the absence of Apoptosis Inducing Factor.

The functional integrity of the central nervous system relies on complex mechanisms in which the mitochondria are crucial actors because of their involvement in a multitude of bioenergetics and biosynthetic pathways. Mitochondrial diseases are among the most prevalent groups of inherited neurological disorders, affecting up to 1 in 5000 adults and despite considerable efforts around the world there is still limited curative treatments. Harlequin mice correspond to a relevant model of recessive X-linked mitochondrial disease due to a proviral insertion in the first intron of the Apoptosis-inducing factor gene, resulting in an almost complete depletion of the corresponding protein. These mice exhibit progressive degeneration of the retina, optic nerve, cerebellum, and cortical regions leading to irremediable blindness and ataxia, reminiscent of what is observed in patients suffering from mitochondrial diseases. We evaluated the progression of cerebellar degeneration in Harlequin mice, especially for Purkinje cells and its relationship with bioenergetics failure and behavioral damage. For the first time to our knowledge, we demonstrated that Harlequin mice display cognitive and emotional impairments at early stage of the disease with further deteriorations as ataxia aggravates. These functions, corresponding to higher-order cognitive processing, have been assigned to a complex network of reciprocal connections between the cerebellum and many cortical areas which could be dysfunctional in these mice. Consequently, Harlequin mice become a suitable experimental model to test innovative therapeutics, via the targeting of mitochondria which can become available to a large spectrum of neurological diseases.