Biology subjects

Bhattacharya, M. R. C.

Publications and source records attributed to Bhattacharya, M. R. C..

4 recordsLinked to original sources

bioRxiv2025

Neuronal endolysosomal acidification relies on interactions between transmembrane protein 184B (TMEM184B) and the vesicular proton pump

Disruption of endolysosomal acidification is a hallmark of several neurodevelopmental and neurodegenerative disorders. Impaired acidification causes accumulation of toxic protein aggregates and disrupts neuronal homeostasis, yet the molecular mechanisms regulating endolysosomal pH in neurons remain poorly understood. A critical regulator of lumenal acidification is the vacuolar ATPase (V-ATPase), a proton pump whose activity depends on dynamic assembly of its V0 and V1 subdomains. In this study, we identify transmembrane protein 184B (TMEM184B) as a novel regulator of endolysosomal acidification in neurons. TMEM184B is an evolutionarily conserved 7-pass transmembrane protein required for synaptic structure and function, and sequence variation in TMEM184B causes neurodevelopmental disorders, but the mechanism for this effect is unknown. We performed proteomic analysis of TMEM184B-interacting proteins and identified enrichment of components involved in endosomal trafficking and function, including the V-ATPase. TMEM184B localizes to early and late endosomes, further supporting a role in the endosomal system. Loss of TMEM184B results in significant reductions in endolysosomal acidification within cultured mouse cortical neurons. This alteration in pH is associated with impaired assembly of the V-ATPase V0 and V1 subcomplexes in the TMEM184B mutant mouse brain, suggesting a mechanism by which TMEM184B promotes flux through the endosomal pathway. Overall, these findings identify a new contributor in maintaining endosomal function and provide a mechanistic basis for disrupted neuronal function in human TMEM184B-associated nervous system disorders. Significance StatementEndolysosomal acidification is essential for neuronal protein homeostasis, yet its regulation in neurons remains poorly understood. Here, we identify TMEM184B as a key regulator of this process, establishing its first known cellular role. We show that TMEM184B interacts with vacuolar ATPase (V-ATPase) components and promotes the assembly of its V0 and V1 subdomains, facilitating lumenal acidification. Loss of TMEM184B disrupts endolysosomal pH in neurons, potentially impairing proteostasis. These findings reveal a critical function for TMEM184B in neuronal maintenance and provide mechanistic insight into its link to neurological disorders. This work advances our understanding of endolysosomal regulation and suggests TMEM184B regulation could improve outcomes in diseases involving lysosomal dysfunction.

neuroscience↗

bioRxiv2022

Transmembrane protein 184B (TMEM184B) promotes expression of synaptic gene networks in the mouse hippocampus

In Alzheimers Disease (AD) and other dementias, hippocampal synaptic dysfunction and loss contribute to the progression of memory impairment. Recent analysis of human AD transcriptomes has provided a list of gene candidates that may serve as drivers of disease. One such candidate is the membrane protein TMEM184B. To evaluate whether TMEM184B contributes to neurological impairment, we asked whether loss of TMEM184B in mice causes gene expression or behavior alterations, focusing on the hippocampus. Because one major risk factor for AD is age, we compared young adult (5-month-old) and aged (15-month-old) wild type and Tmem184b-mutant mice to assess the dual contributions of age and genotype. TMEM184B loss altered expression of pre- and post-synaptic transcripts by 5 months and continued through 15 months, specifically affecting genes involved in synapse assembly and neural development. Wnt-activated enhancer elements were enriched among differentially expressed genes, suggesting an intersection with this pathway. Few differences existed between young adult and aged mutants, suggesting that transcriptional effects of TMEM184B loss are relatively constant. To understand how TMEM184B disruption may impact behaviors, we evaluated memory using the novel object recognition test and anxiety using the elevated plus maze. Young adult Tmem184b-mutant mice show normal object discrimination, suggesting a lack of memory impairment at this age. However, mutant mice showed decreased anxiety, a phenotype seen in some neurodevelopmental disorders. Taken together, our data suggest that TMEM184B is required for proper synaptic gene expression and anxiety-related behavior and is more likely to be linked to neurodevelopmental disorders than to dementia.

neuroscience↗

bioRxiv2021

The Drosophila TMEM184B ortholog Tmep ensures proper locomotion by restraining ectopic firing at the neuromuscular junction

TMEM184B is a putative seven-pass membrane protein that promotes axon degeneration after injury. TMEM184B mutation causes aberrant neuromuscular architecture and sensory and motor behavioral defects in mice. The mechanism through which TMEM184B causes neuromuscular defects is unknown. We employed Drosophila melanogaster to investigate the function of the TMEM184B ortholog, Tmep (CG12004) at the neuromuscular junction. We show that Tmep is required for full adult viability and efficient larval locomotion. Tmep mutant larvae have a reduced body contraction rate compared to controls, with stronger deficits in females. Surviving adult Tmep mutant females show "bang sensitivity," a phenotype associated with epileptic seizures. In recordings from body wall muscles, Tmep mutants show substantial hyperexcitability, with many post-synaptic potentials fired in response to a single stimulation, consistent with a role for Tmep in restraining synaptic excitability. Neuromuscular junctions in Tmep mutants show modest structural defects and satellite boutons, which could also contribute to poor locomotor performance. Tmep is expressed in endosomes and synaptic vesicles within motor neurons, suggesting a possible role in synaptic membrane trafficking. Using RNAi knockdown, we show that Tmep is required in motor neurons for proper larval locomotion and excitability. Locomotor defects can be rescued by presynaptic knock-down of endoplasmic reticulum calcium channels or by reducing evoked release probability, suggesting that excess synaptic activity drives behavioral deficiencies. Our work establishes a critical function for the TMEM184B ortholog Tmep in the regulation of synaptic transmission and locomotor behavior.

neuroscience↗

bioRxiv2020

TMEM184B controls pruriceptor specification and function

Nociceptive and pruriceptive neurons in the dorsal root ganglia (DRG) convey sensations of pain and itch to the spinal cord, respectively. One subtype of mature DRG neurons, comprising about 5% of neurons in the ganglia, is responsible for sensing mediators of acute itch and atopic dermatitis, including the cytokine IL-31. How itch-sensitive (pruriceptive) neurons are specified is unclear. Here we show that Tmem184b, a gene with roles in axon degeneration and nerve terminal maintenance, is required for the expression of a large cohort of itch receptors, including those for IL-31, Leukotriene C4, and Histamine. Male and female mice lacking Tmem184b show reduced responses to IL-31, but maintain normal responses to pain and mechanical force, indicating a specific behavioral defect in pruriception. Calcium imaging experiments indicate that a reduction in IL-31 induced calcium entry is a likely contributor to this phenotype. We identify an early failure of proper Wnt-dependent transcriptional signatures and signaling components in Tmem184b mutant mice that may explain the improper DRG neuronal subtype specification. Accordingly, lentiviral re-expression of Tmem184b in mutant embryonic neurons restores Wnt signatures. Together, these data demonstrate that Tmem184b promotes adult somatosensation through developmental Wnt signaling and promotion of proper pruriceptive gene expression. Our data illuminate a new key regulatory step in the processes controlling the establishment of diversity in the somatosensory system.

neuroscience↗