Keeping it together: Neuronal organelle function in health and disease

Neurons are highly polarized cells with distinct compartments — soma, dendrites, axons, and synaptic domains — housing specialized organelles critical for synaptic activity and energy supply. Organelle dysfunction and disruptions in these systems are strongly linked to neurode- generative diseases like tauopathies, where pathological tau mislocalizes to dendrites, impairing neuronal function and survival. The mechanisms connecting compartment-specific degener- ation and organelle dysfunction remain poorly understood. Therefore, the studies in this thesis investigated neuronal organelle function and dysfunction across distinct subcellular compart- ments, in both under physiological conditions and in the context of tau protein pathology. Specifically, this work focused on: (1) elucidating the role of endosomal sorting mediated by Sortin Nexin 4 (SNX4) in synapse function, (2) characterizing the impact of tau pathology on endosomal morphology and function, and (3) examining the compartment-specific effects of tau pathology on organelle function and dendrite integrity.