Endolysosomal Function in Neuronal Maintenance




Jin, Eugene Jennifer

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Endolysosomal degradation of membrane proteins is crucial for the maintenance of synaptic function and neuronal health. Neurons can live for the lifetime of an organism and therefore rely on robust membrane turnover mechanisms to clear old, dysfunctional, excess or possibly also functional membrane proteins. A key regulator of canonical endolysosomal degradation is Rab7, a ubiquitous small GTPase required for endosomal maturation. Based on the observation that Rab7 expression is strongly neuron-enriched during Drosophila development, I first tested specific requirement of Rab7 in neurons. I found that loss of rab7 does not affect development, but causes activity-dependent degeneration that starts at synapses in Drosophila photoreceptors. Four point mutations in Rab7 are associated with the peripheral neuropathy Charcot-Marie-Tooth Type 2B (CMT2B) disease and my data suggest a partial loss of function mechanism. Together, these findings highlight that neurons are particularly sensitive to the dosage of Rab7-dependent endolysosomal degradation. Several other membrane turnover mechanisms, including autophagy and a neuron-specific branch of the endolysosomal system, called 'neuronal-sort-and-degrade' (NSD), are also required for neuronal maintenance. However, it remained unclear what cargoes these different membrane turnover mechanisms degrade, and where cargoes are degraded. Given that NSD is a neuron-specific mechanism whereas Rab7-dependent endolysosomal degradation and autophagy are ubiquitous mechanisms, I hypothesized that NSD may specifically sort and degrade synaptic membrane proteins, whereas the Rab7-dependent canonical endolysosomal degradation and autophagy unbiasedly degrade all membrane proteins. I tested this hypothesis by live imaging of an acidification-sensing degradation probe for a synaptic vesicle (SV)-specific cargo and a general membrane cargo to directly and quantitatively measure the sorting and degradation of these cargoes at Drosophila photoreceptor axon terminals. I found that both cargoes are sorted and degraded locally at axon terminals. Interestingly, the two cargoes are sorted into two distinct 'hub compartments' for degradation. Rab7 and NSD are required for the sorting and degradation of the two cargoes separately: sorting and degradation of general cargo is Rab7-dependent, whereas that of SV cargo is NSD-dependent. In sum, this work highlights neuron-specific mechanisms for cargo-specific membrane protein degradation that keep synapses healthy and functional.

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The file named "JIN-DISSERTATION-2018.pdf" is the primary dissertation file. All other files ("*.mp4") are supplemental files and may be viewed individually.

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