Frataxin Deficit Leads to Reduced Dynamics of Growth Cones in Dorsal Root Ganglia Neurons of Friedreich’s Ataxia YG8sR Model: A Multilinear Algebra Approach

Abstract

Computational techniques for analyzing biological images offer a great potential to enhance our knowledge of the biological processes underlying disorders of the nervous system. Friedreich’s Ataxia (FRDA) is a rare progressive neurodegenerative inherited disorder caused by the low expression of frataxin, which is a small mitochondrial protein. In FRDA cells, the lack of frataxin promotes primarily mitochondrial dysfunction, an alteration of calcium (Ca2+) homeostasis and the destabilization of the actin cytoskeleton in the neurites and growth cones of sensory neurons. In this paper, a computational multilinear algebra approach was used to analyze the dynamics of the growth cone and its function in control and FRDA neurons. Computational approach, which includes principal component analysis and a multilinear algebra method, is used to quantify the dynamics of the growth cone (GC) morphology of sensory neurons from the dorsal root ganglia (DRG) of the YG8sR humanized murine model for FRDA. It was confirmed that the dynamics and patterns of turning were aberrant in the FRDA growth cones. In addition, our data suggest that other cellular processes dependent on functional GCs such as axonal regeneration might also be affected. Semiautomated computational approaches are presented to quantify differences in GC behaviors in neurodegenerative disease. In summary, the deficiency of frataxin has an adverse effect on the formation and, most importantly, the growth cones’ function in adult DRG neurons. As a result, frataxin deficient DRG neurons might lose the intrinsic capability to grow and regenerate axons properly due to the dysfunctional GCs they build.

Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype

“…The concentration of human frataxin protein was reduced in YG8sR in all tissues tested compared to Y47R and even more than in the YG8sR(200) for the cerebellum (i.e., 70% in the YG8sR(200) and 19% in YG8sR). Considering that YG8sR mice have a human frataxin transgene containing 250–300 GAA repeats responsible for low human frataxin expression, these mice remain a good model to study the effects of frataxin reduction [ 36 ], or to try to increase the frataxin expression by some treatments [ 37 , 38 ] or even through genetic modifications using the CRISPR-Cas9 system to delete the GAA repeat [ 19 , 20 ]. All these studies are essential to understanding the mechanism and interaction between the frataxin protein and other proteins or enzymes but at some point, it becomes essential to have a good mouse model that recreates the symptoms of Friedreich ataxia and allows for the detection of functional improvements with treatment.…”