Finally, a method that allows identifying and quantifying C1, C2, and sFL, together with FL-PrPC, will be useful for a comprehensive appraisal of PrPC levels and possible alterations in proteoform composition in PrPC-lowering therapies or in the screening of such drugs, as well as for studying both possibly meaningful disease-related alterations in the proteoform pool and an influence of the PrPC proteoforms on the progression of neurodegenerative diseases. Here, PRNP is linked to neurodegenerative disease.