Removal of proteinase K resistant αSyn species does not correlate with cell survival in a virus vector-based Parkinson's disease mouse model

Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

“…Reduced activity of protein degradation systems, such as proteasomes, autophagic systems and lysosomes occur in patients with synucleinopathies. Therefore, the activation of autophagy gives hope for future therapeutic applications [ 36 , 79 , 82 , 83 ]. There are approaches that are not aimed at α-synuclein in a straight line but affect it indirectly.…”

“…Therefore, this enzyme may be considered a possible target in synucleinopathies [ 36 , 62 ]. Other autophagy activation methods also give hope for future therapeutic applications [ 82 ].…”

“…These strategies may include the fusion of effective inhibitors with a cell-penetrating peptide-based tag or conjugation to other types of delivery constructs such as brain-penetrating nanoparticles. The inhibitor designs are also genetically encodable, including viral delivery, another possible transport mechanism [ 82 ].…”

“…An example of an approach based on the activation of autophagy gives hope for future therapeutic applications [ 82 ]. For instance, a small molecular inhibitor for prolyl oligopeptidase, KYP-2047, relieves α-synuclein-induced toxicity in various PD models by inducing autophagy and preventing α-synuclein aggregation, without reducing soluble α-synuclein oligomers.…”

“…These findings indicate that when considering potential drug treatment for synucleinopathies, it is critical to characterize the α-synuclein aggregation process in detail, identifying the most toxic forms of α-synuclein. The authors also assume that previous failure to use α-synuclein aggregation inhibitors may be explained by the fact that removal of random α-synuclein aggregates forms does not provide neuroprotection [ 82 ].…”