Year: 2025
Type: dissertation
Abstract: Altered endolysosomal acidification has been associated with neurological diseases, including lysosomal storage disorders and Alzheimer's Disease. In these conditions, reduced acidification of these compartments leads to the accumulation of cytotoxic proteins, impaired neuronal homeostasis, and ultimately, neuronal death. This dissertation identifies transmembrane protein 184B (TMEM184B), as a novel regulator of endolysosomal acidification and neural development. Using RNA-sequencing, behavioral assays, immunoprecipitation-mass spectrometry (IP-MS), confocal imaging, and co-immunoprecipitation assays, this study indicates that TMEM184B promotes endolysosomal acidification, supports synaptic development, and maintains neuronal function over time. Tmem184b-deficient mice display altered expression of synaptic genes by five months of age, particularly in synapse assembly and neural development, with Wnt-activated enhancer elements enriched. Behavioral analysis indicates normal object recognition but reduced anxiety, a common observation in certain neurodevelopmental disorders. Proteomic analysis of binding partners revealed that TMEM184B interacts with multiple proteins involved in endosomal trafficking, including the vesicular proton pump (V-ATPase). TMEM184B predominantly localizes to early and late endosomes in the cell. In the absence of TMEM184B, endolysosomal acidification is diminished, consistent with impaired V-ATPase subdomain assembly. Together, these findings suggest a novel role for TMEM184B in endolysosomal homeostasis and neural development, offering insights into its potential implications in both neurodevelopmental and neurodegenerative diseases.
Authors: Wright, Elizabeth, Wright, Elizabeth
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W7025215369