Neurodegenerative foldopathies are characterized by aberrant folding of diseased modified proteins, which are major constituents of the intracellular and extracellular lesions. These lesions correlate with the cognitive and/or motor impairment seen in these diseases. The majority of the disease modified proteins in neurodegenerative foldopathies belongs to the group of proteins termed as intrinsically disordered proteins (IDPs). Several independent studies have showed that abnormal protein processing constitutes the key pathological feature of these disorders. The current review focuses on protein truncation as a common denominator of neurodegenerative foldopathies, which is considered to be the major driving force behind the pathological metamorphosis of brain IDPs. The aim of the review is to emphasize the key role of the protein truncation in the pathogenic pathways of neurodegenerative diseases. A deeper understanding of the complex downstream processing of the IDPs, resulting in the generation of pathologically modified proteins might be a prerequisite for the successful therapeutic strategies of several fatal neurodegenerative diseases.