Deciphering the neuropathology of c9ALS/FTD and Spinocerebellar Ataxia Type 36

  • 9:00 am (PDT)
Speakers: Zachary McEachin, PhD, Emory University School of Medicine

c9 Amyotrophic Lateral Sclerosis (c9ALS)/Frontotemporal Dementia (FTD) and Spinocerebellar Ataxia Type 36 (SCA36) are diseases characterized by intronic hexanucleotide repeats that differ by only one nucleotide in the repeating unit. Despite being clinically distinct, similar pathogenic mechanisms have been proposed to underlie neurodegeneration in these two diseases. In this webinar, we compare these “genetic doppelgängers” using the nCounter® Neuropathology Panel and GeoMx® Digital Spatial Profiler (DSP) to provide insight into their neuropathology. We demonstrate, that similar to c9ALS/FTD, sense and antisense dipeptide repeat proteins (DPRs) are produced in SCA36.  We show that poly(GP) is more abundant in SCA36 compared to c9ALS/FTD patient tissue due to canonical AUG-mediated translation from intron-retained GGCCUG repeat RNAs. However, the frequency of the antisense RAN translation product poly(PR) is comparable between c9ALS/FTD and SCA36 patient samples. Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species and no TDP-43 pathology is present. Our data provide evidence that the formation of aggregate-prone chimeric dipeptide repeat (cDPR) species underlies the divergent DPR pathology between c9ALS/FTD and SCA36. These findings reveal key differences in the translation, solubility and protein aggregation of DPRs found in c9ALS/FTD and SCA36.

For Research Use Only.  Not for Use in Diagnostic Procedures.