Friedreich's ataxia, mitochondrial biogenesis, and neurodegeneration

University Of California At Davis, Davis CA

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Abstract

Friedreich's ataxia (FA) is the most common recessive inherited ataxia, comprising about half of patients seen in ataxia clinics. FA is caused by the deficiency of a single mitochondrially-localized protein, frataxin, to about 10% residual, and the neuropathophysiological and cardiological consequences of this mitochondrial protein depletion are ultimately lethal. We have recently demonstrated for the first time that there is a mitochondrial biogenesis defect proportional to the frataxin defect in FA patient fibroblasts and blood lymphocytes of living FA patients, and decreased in multiple neural and muscle tissues in FA mouse models. This depletion of mitochondrial biogenesis and function could turn out to be a major driver of FA pathophysiology and neurodegeneration, i.e. our premise is that frataxin decline?mitobiogenic decline?FA neuropathophysiology and neurodegeneration. Furthermore, because the mitobiogenesis defect occurs in blood lymphocytes of living FA patients in proportion to their frataxin deficiency, it could provide an important blood biomarker of disease pathophysiology and/or patient outcome for clinical drug trials. Thus we propose to investigate the contribution of the mitobiogenic defect to the ataxic pathomechanism in the best mouse model of FA, the FXNKD mouse (Aim 1), the mechanism by which frataxin decrease leads to the mitobiogenic defect (Aim 2), and the relevance and stability of the mitobiogenic defect in peripheral blood lymphocytes of living FA patients, and also mitobiogenic defects in autoptic FA human target tissues that experience neurodegeneration and cardiodegeneration (Aim 3). These studies will clarify the pathomechanistic contribution of the frataxin-dependent defect in mitochondrial biogenesis we identified to the ataxia in the best available mouse model of FA, and its value as a biomarker, and its relationship to the pathomechanism in the human condition.