Clinical, Diagnostic Biomarkers, Pathogenesis, Preclinical

Development of non-human primate MSA model and imaging biomarker of mitochondrial activity in MSA

One of the major obstacles to overcome MSA is the lack of an animal model that recapitulates the pathological features of MSA. Recent animal studies have shown that injection of different alpha-synuclein (αSyn) conformers or strains induces different αSyn pathological features in animal brains. In addition, a recent cryo- EM study revealed the unique conformation of αSyn filaments in MSA brains. Therefore, to faithfully model MSA in animals, we should inject αSyn aggregates extracted from MSA brains into animal brains. We have previously established a biochemical extraction method to obtain highly concentrated pathological αSyn aggregates from frozen synucleinopathy brains.

In this project, we will inject non-human primate marmosets with the highly concentrated MSA αSyn aggregates and perform behavioral and pathological analyses up to 12 months post-injection to establish them as a novel MSA model. Meanwhile, accumulating evidence suggests that mitochondrial dysfunction is involved in the pathophysiology of MSA. In vivo mitochondrial activity can be assessed using a recently developed PET probe, [18F]BCPP-EF, which binds to mitochondrial complex I. Taking advantage of the applicability of marmosets to brain imaging studies, we will perform BCPP-EF-PET in the MSA marmosets and analyze the correlations of BCPP-EF uptake (mitochondrial function) with pathological and behavioral features.

Furthermore, in this project, we will perform BCPP-EF-PET on patients with MSA and analyze the correlations of BCPP-EF uptake with clinical data, including a clinical rating scale for MSA (UMSARS) and MRI. Overall, the novel MSA marmoset model would provide opportunities to examine the pathological mechanisms of MSA and develop disease-modifying therapy. The BCPP-EF-PET imaging in both the MSA marmosets and patients would clarify the contribution of mitochondrial dysfunction to MSA pathophysiology and the potential of mitochondrial activity as a novel imaging biomarker in MSA.