α-Syn and Tau interfere with protein homeostasis. Overview of the steps involved in the three distinct autophagy–lysosomal degradation pathways and the UPS. The PD-related proteins, LRRK2, SYNJ1, and EndoA, regulate the induction of synaptic autophagy. During macroautophagy, a phagophore forms around cytoplasmic components to remove substrates. The resulting autophagosome fuses with a lysosome to form a degrading autolysosome. CMA targets proteins containing a KFERQ-like motif, which is common in many synaptic proteins, including α-Syn and Tau, and mediates their direct translocation into lysosomes. eMI involves the uptake of substrates by invagination of the endosomal membrane. Both α-Syn and Tau affect various steps in these pathways, either inhibiting (indicated by red inhibition symbols) beneficial processes or promoting (indicated by red arrows) harmful routes. α-Syn could be a negative regulator of synaptic autophagy by inhibiting EndoA (indicated with “?”). Disruption of the protein degradation machinery will then also negatively affect the turnover of α-Syn and Tau as well as other proteins, further compromising the overall proteostasis. The cumulative impact on the synaptic proteome caused by α-Syn and Tau likely contributes to synaptic dysfunction and proteostasis collapse during the prodromal phase of neurodegenerative diseases.