News about the simposium of ataxias
ADVANCES ABOUT THE SIMPOSIUM OF ATAXIAS
Novel molecular mechanisms and biomarker studies in the SCAs.
Xiaofei Du, Katherine Hekman, Ashley Brouilette, Jacqueline T. Bernard, Ana Solodkin, Gulin Oz and Christopher M. Gomez.
Department of Neurology, AMB S237, MC2030, The University of Chicago, 5841 S. Maryland, Chicago IL, 60637, Tele: 773-702-6390 , Fax: 773-834-3232
The spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of disorders with clinically overlapping phenotypes arising from Purkinje cell degeneration, cerebellar atrophy and varying degrees of degeneration of other gray matter regions. The absence of clear molecular genetic mechanisms in the SCAs impedes development of rational therapies, while the complex clinical phenotypes have prevented efficient plotting disease progression. We describe two new molecular mechanisms in the SCAs and our efforts to identify novel neuroanatomical, functional and neurochemical biomarkers in the SCAs. We have characterized the molecular and cellular mechanisms for SCA6 and SCA26. We have identified a novel pathological protein in SCA6, a second gene product encoded by the CACNA1A gene, a1ACT, that normally functions as a transcription factor important in Purkinje cell development. The polyglutamine expansion interrupts this function and renders the a1ACT toxic. The disease protein in SCA26 is eukaryotic elongation factor, type 2, bearing a missense mutation, P596H, that alters translational fidelity and proteostasis. These findings support the idea of selective vulnerability of Purkinje cells to protein misfolding in either the nucleus or cytoplasm.
Using spectral mode optical coherence tomography we have found that measurement of the thickness of the retinal nerve fiber layer and macula may distinguish between SCA1, 2, 3, 6 and MSA-C, suggesting that serial measurements may track with disease severity. Using the BOLD signal measured during fMRI at 3T we have observed that the intrinsic organization of cerebellar lamellar compartments deteriorates as a function of disease severity and duration in SCA1. Using ultrafast pulse sequences to discriminate multiple neurochemicals in selected cerebellar and brainstem voxels at 4T we have found disease and stage-specific neurochemical profiles in SCA1, 2, 3 and SCA6. Finally, we studied CSF using ELISA targeted a set of candidate proteins we identified significant differences in levels of tau protein and a synuclein among patients with SCA1, 2, 6 and MSA-C.
Thus, evidence suggests that cerebellar Purkinje cells are uniquely vulnerable to a wide variety of genetic/cellular insults. Probing the basis for this vulnerability may be the only route to identifying a broadly applicable therapy. A variety of imaging and neurochemical methodologies show promise in identifying disease-specific and stage-specific biomarkers.