Expect Delays: The Parkinson's Disease Risk Factor TMEM175 Regulates Endocytic Traffic

Author

Daniel R. Montagna, University of Massachusetts BostonFollow

Date of Award

12-2024

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology/Molecular, Cellular, and Organismal Biology

First Advisor

Linda Huang

Second Advisor

Paul A. Temkin

Third Advisor

Alexey Veraksa, Kellee Siegfried-Harris, Roshanak Irannejad

Abstract

Endocytic traffic is the coordinated process by which membrane, membrane-associated proteins, transmembrane proteins, and soluble luminal cargo distribute throughout the cell in the functionally interconnected membrane-bound compartments known collectively as the endocytic network. Regulated endocytic traffic is critical to nutrient uptake, clearance of cellular material targeted for degradation, and spatiotemporal organization of intracellular signaling events. In neurons, endocytic traffic influences neuronal activity by refining receptor composition at specialized domains such as the synapse, and by targeting receptors for lysosomal degradation to ensure proper cellular and subdomain specific sensitivity to extracellular signaling molecules. My work focuses on the predominantly lysosomal H+ channel TMEM175 – loss of which is associated with Parkinson’s disease (PD) risk. In cells, TMEM175 depletion causes defects to lysosomal and mitochondrial function – both of which are common features of cellular PD models. Rather than such specific lysosomal influence, I find that TMEM175 broadly regulates the endocytic network. In TMEM175-knockout cells, I detected increased segregation of fluid-phase endocytic cargo from hydrolytically active compartments, indicating a trafficking basis for decreased cargo hydrolysis. Furthermore, I demonstrated that TMEM175 depletion delays both receptor-mediated endocytosis and subsequent recycling – disinhibiting receptor signaling from both the plasma membrane and from endocytic compartments. In neurons, TMEM175 depletion disrupts calcium handling and regulation of spontaneous calcium oscillations – a significant neurodegenerative liability in PD-vulnerable dopaminergic neurons. In sum, my work represents a departure from interpreting TMEM175 as a facilitator of hydrolytic function. Instead, I place emphasis on its role in organization of the endocytic network, dysregulated signaling, and the potential neurodegenerative burden such dysregulated activity may confer upon PD-vulnerable dopaminergic neurons.

Comments

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Recommended Citation

Montagna, Daniel R., "Expect Delays: The Parkinson's Disease Risk Factor TMEM175 Regulates Endocytic Traffic" (2024). Graduate Doctoral Dissertations. 1026.
https://scholarworks.umb.edu/doctoral_dissertations/1026