Prion protein pathology in Ubiquilin 2 models of ALS

Mutations in UBQLN2 cause ALS and frontotemporal dementia (FTD). The pathological signature in UBQLN2 cases is deposition of highly unusual types of inclusions in the brain and spinal cord that stain positive for UBQLN2. However, what role these inclusions play in pathogenesis remains unclear. Here we show cellular prion protein (PrP^C) is found in UBQLN2 inclusions in both mouse and human neuronal induced pluripotent (IPSC) models of UBQLN2 mutations, evidenced by the presence of aggregated forms of PrP^C with UBQLN2 inclusions. Turnover studies indicated that the P497H UBQLN2 mutation slows PrP^C protein degradation and leads to mislocalization of PrP^C in the cytoplasm. Immunoprecipitation studies indicated UBQLN2 and PrP^C bind together in a complex. The abnormalities in PrP^C caused by UBQLN2 mutations may be relevant in disease pathogenesis.