In Vivo Molecular Signatures of Cerebellar Pathology in Spinocerebellar Ataxia Type 3

Background No treatment exists for the most common dominantly inherited ataxia Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3). Successful evaluation of candidate therapeutics will be facilitated by validated noninvasive biomarkers of disease pathology recapitulated by animal models. Objective We sought to identify shared in vivo neurochemical signatures in two mouse models of SCA3 that reflect the human disease pathology. Methods Cerebellar neurochemical concentrations in homozygous YACMJD84.2 (Q84/Q84) and hemizygous CMVMJD135 (Q135) mice were measured by in vivo magnetic resonance spectroscopy at 9.4 tesla. To validate the neurochemical biomarkers, levels of neurofilament medium (NFL; indicator of neuroaxonal integrity) and myelin basic protein (MBP; indicator of myelination) were measured in cerebellar lysates from a subset of mice and patients with SCA3. Finally, NFL and MBP levels were measured in the cerebellar extracts of Q84/Q84 mice upon silencing of the mutantATXN3gene. Results Both Q84/Q84 and Q135 mice displayed lowerN-acetylaspartate than wild-type littermates, indicating neuroaxonal loss/dysfunction, and lowermyo-inositol and total choline, indicating disturbances in phospholipid membrane metabolism and demyelination. Cerebellar NFL and MBP levels were accordingly lower in both models as well as in the cerebellar cortex of patients with SCA3 than controls. Importantly,N-acetylaspartate and total choline correlated with NFL and MPB, respectively, in Q135 mice. Long-term sustained RNA interference (RNAi)-mediated reduction ofATXN3levels increased NFL and MBP in Q84/Q84 cerebella. Conclusions N-acetylaspartate,myo-inositol, and total choline levels in the cerebellum are candidate biomarkers of neuroaxonal and oligodendrocyte pathology in SCA3, aspects of pathology that are reversible by RNAi therapy. (c) 2020 International Parkinson and Movement Disorder Society