Autophagy, the process of degrading cytosolic components in lysosomes, is crucial for neuronal homeostasis and its dysfunction has been linked to various neurodegenerative disorders. The review discusses the diverse reasons behind autophagic failure in degenerating neurons, highlighting the importance of understanding the specific steps affected in each disorder to develop targeted therapeutic approaches. It covers the different types of autophagic dysfunction observed in common neurodegenerative disorders and explores the potential of autophagic variants and interactions with non-autophagic proteolytic systems as future therapeutic targets. The authors emphasize the need to identify the specific autophagic step(s) affected in different neuronal pathologies to guide therapeutic interventions. They also discuss the compensatory cross-talk between autophagy and other proteolytic systems, such as the ubiquitin-proteasome system and endocytosis, and the potential therapeutic implications of these interactions.Autophagy, the process of degrading cytosolic components in lysosomes, is crucial for neuronal homeostasis and its dysfunction has been linked to various neurodegenerative disorders. The review discusses the diverse reasons behind autophagic failure in degenerating neurons, highlighting the importance of understanding the specific steps affected in each disorder to develop targeted therapeutic approaches. It covers the different types of autophagic dysfunction observed in common neurodegenerative disorders and explores the potential of autophagic variants and interactions with non-autophagic proteolytic systems as future therapeutic targets. The authors emphasize the need to identify the specific autophagic step(s) affected in different neuronal pathologies to guide therapeutic interventions. They also discuss the compensatory cross-talk between autophagy and other proteolytic systems, such as the ubiquitin-proteasome system and endocytosis, and the potential therapeutic implications of these interactions.