Martha Bhattacharya

Interests

No activities entered.

Courses

No activities entered.

Scholarly Contributions

Journals/Publications

• Chapman, K. A., Ullah, F., Yahiku, Z. A., Khan, S., Kodiparthi, S. V., Kellaris, G., White, H. G., Powell, A. T., Correia, S. P., Stödberg, T., Sofocleous, C., Marinakis, N. M., Fryssira, H., Tsoutsou, E., Traeger-Synodinos, J., Accogli, A., Sciruicchio, V., Salpietro, V., Striano, P., , Muss, C., et al. (2025). Pathogenic variants in TMEM184B cause a neurodevelopmental syndrome associated with alteration of metabolic signaling. American Journal of Human Genetics, 112(Issue 10). doi:10.1016/j.ajhg.2025.08.004
  More info

  Transmembrane protein 184B (TMEM184B) is an endosomal 7-pass transmembrane protein with evolutionarily conserved roles in synaptic structure and axon degeneration. We report six pediatric cases who have de novo heterozygous variants in TMEM184B; five individuals harbor a rare missense variant, and one individual has an mRNA splice site change. This cohort is unified by overlapping neurodevelopmental deficits including developmental delay, corpus callosum hypoplasia, seizures, and/or microcephaly. TMEM184B is predicted to contain a pore domain wherein four of five human disease-associated missense variants cluster. Structural modeling suggests that all missense variants alter TMEM184B protein stability. To understand the contribution of TMEM184B to neural development in vivo, we knocked down the TMEM184B ortholog in zebrafish and observed microcephaly and reduced anterior commissural axons, aligning with symptoms of affected individuals. Ectopic expression of TMEM184B c.550A>G (p.Lys184Glu) and c.484G>A (p.Gly162Arg) variants cause reduced head size and body length, indicating dominant effects, while three other variants show haploinsufficiency. None of the variants are able to rescue the knockdown phenotype. Human induced pluripotent stem cells with monoallelic production of p.Lys184Glu show mRNA disruptions in key metabolic pathways including those controlling mechanistic target of rapamycin activity. Expression of p.Lys184Glu and c.863G>C (p.Gly288Ala) increased apoptosis in cell lines, and p.Lys184Glu increased nuclear localization of transcription factor EB, consistent with a cellular starvation state. Together, our data indicate that TMEM184B variants cause cellular metabolic disruption and result in abnormal neural development.
• Wright, E. B., Larsen, E. G., Padilla-Rodriguez, M., Langlais, P. R., & Bhattacharya, M. R. (2025). TMEM184B modulates endolysosomal acidification via the vesicular proton pump. Journal of Cell Science, 138(Issue 15). doi:10.1242/jcs.263908
  More info

  Disruption of endolysosomal acidification causes toxic protein accumulation and neuronal dysfunction linked to neurodevelopmental and neurodegenerative disorders. However, the molecular mechanisms regulating neuronal endolysosomal pH remain unclear. Transmembrane protein 184B (TMEM184B) is a conserved seven-pass transmembrane protein that is essential for synaptic function, and its sequence disruption is associated with neurodevelopmental disorders. Here, we identify TMEM184B as a key regulator of endolysosomal acidification. TMEM184B localizes to early and late endosomes, and proteomic analysis confirms that TMEM184B interacts with endosomal proteins, including the vacuolar ATPase (V-ATPase), a multi-subunit proton pump crucial for lumenal acidification. Tmem184b-mutant mouse cortical neurons have reduced endolysosomal acidification compared to wild-type neurons. We find reductions in V-ATPase complex assembly in Tmem184b-mutant mouse brains, suggesting that TMEM184B facilitates endosomal flux by promoting V-ATPase activity. These findings establish TMEM184B as a regulator of neuronal endolysosomal acidification and provide mechanistic insight into its role in TMEM184B-associated nervous system disorders.
• Bhattacharya, M. R. (2023). A nerve-wracking buzz: lessons from models of peripheral neuropathy and axon degeneration. Frontiers in aging neuroscience, 15, 1166146.
  More info

  The degeneration of axons and their terminals occurs following traumatic, toxic, or genetically-induced insults. Common molecular mechanisms unite these disparate triggers to execute a conserved nerve degeneration cascade. In this review, we will discuss how models of peripheral nerve injury and neuropathy in have led the way in advancing molecular understanding of axon degeneration and nerve injury pathways. Both neuron-intrinsic as well as glial responses to injury will be highlighted. Finally, we will offer perspective on what additional questions should be answered to advance these discoveries toward clinical interventions for patients with neuropathy.
• Bhattacharya, M. R. (2023). A nerve-wracking buzz: lessons from Drosophila models of peripheral neuropathy and axon degeneration. Frontiers in Aging Neuroscience, 15(Issue). doi:10.3389/fnagi.2023.1166146
  More info

  The degeneration of axons and their terminals occurs following traumatic, toxic, or genetically-induced insults. Common molecular mechanisms unite these disparate triggers to execute a conserved nerve degeneration cascade. In this review, we will discuss how models of peripheral nerve injury and neuropathy in Drosophila have led the way in advancing molecular understanding of axon degeneration and nerve injury pathways. Both neuron-intrinsic as well as glial responses to injury will be highlighted. Finally, we will offer perspective on what additional questions should be answered to advance these discoveries toward clinical interventions for patients with neuropathy.
• Wright, E. B., Larsen, E. G., Coloma-Roessle, C. M., Hart, H. R., & Bhattacharya, M. R. (2023). Transmembrane protein 184B (TMEM184B) promotes expression of synaptic gene networks in the mouse hippocampus. BMC genomics, 24(1), 559.
  More info

  In Alzheimer's 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.
• Cho, T. S., Beigaitė, E., Klein, N. E., Sweeney, S. T., & Bhattacharya, M. R. (2022). The Putative Drosophila TMEM184B Ortholog Tmep Ensures Proper Locomotion by Restraining Ectopic Firing at the Neuromuscular Junction. Molecular Neurobiology, 59(Issue 4). doi:10.1007/s12035-022-02760-3
  More info

  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 closely related gene, 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. In recordings from body wall muscles, Tmep mutants show substantial hyperexcitability, with many postsynaptic potentials fired in response to a single stimulation, consistent with a role for Tmep in restraining synaptic excitability. Additional branches and satellite boutons at Tmep mutant neuromuscular junctions are consistent with an activity-dependent synaptic overgrowth. 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, and that its reduction increases levels of presynaptic calcium. Locomotor defects can be rescued by presynaptic knockdown of endoplasmic reticulum calcium channels or by reducing evoked release probability, further suggesting that excess synaptic activity drives behavioral deficiencies. Our work establishes a critical function for Tmep in the regulation of synaptic transmission and locomotor behavior.
• Cho, T. S., Beigaitė, E., Klein, N. E., Sweeney, S. T., & Bhattacharya, M. R. (2022). The Putative Drosophila TMEM184B Ortholog Tmep Ensures Proper Locomotion by Restraining Ectopic Firing at the Neuromuscular Junction. Molecular neurobiology, 59(4), 2605-2619.
  More info

  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 closely related gene, 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. In recordings from body wall muscles, Tmep mutants show substantial hyperexcitability, with many postsynaptic potentials fired in response to a single stimulation, consistent with a role for Tmep in restraining synaptic excitability. Additional branches and satellite boutons at Tmep mutant neuromuscular junctions are consistent with an activity-dependent synaptic overgrowth. 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, and that its reduction increases levels of presynaptic calcium. Locomotor defects can be rescued by presynaptic knockdown of endoplasmic reticulum calcium channels or by reducing evoked release probability, further suggesting that excess synaptic activity drives behavioral deficiencies. Our work establishes a critical function for Tmep in the regulation of synaptic transmission and locomotor behavior.
• Larsen, E. G., Cho, T. S., McBride, M. L., Feng, J., Manivannan, B., Madura, C., Klein, N. E., Wright, E. B., Wickstead, E. S., Garcia-Verdugo, H. D., Jarvis, C., Khanna, R., Hu, H., Largent-Milnes, T. M., & Bhattacharya, M. R. (2022). Transmembrane protein TMEM184B is necessary for interleukin-31-induced itch. Pain, 163(5), e642-e653.
  More info

  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 6% to 8% 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 transmembrane protein 184B (TMEM184B), a protein with roles in axon degeneration and nerve terminal maintenance, is required for the expression of a large cohort of itch receptors, including those for interleukin 31 (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 IL-31-induced pruriception. Calcium imaging experiments indicate that a reduction in IL-31-induced calcium entry is a likely contributor to this phenotype. We identified 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.
• Bhattacharya, M. R. (2020). A Chemotherapy-Induced Peripheral Neuropathy Model in Drosophila melanogaster. Methods in molecular biology (Clifton, N.J.), 2143, 301-310.
  More info

  Peripheral neuropathies are one of the largest categories of neurodegenerative diseases. To investigate their mechanisms, many in vitro and in vivo models can be employed. Here we present a protocol for the induction of chemotherapy-induced peripheral neuropathy (CIPN) in the Drosophila melanogaster (fruit fly) model system. Using a clinically relevant degeneration initiator, paclitaxel (taxol), it is possible to model many aspects of axon and dendrite degeneration while in a genetically tractable, in vivo system. In this protocol, we feed larval stage Drosophila neurotoxic chemotherapy drugs during the duration of larval development, followed by dissection and imaging of genetically labeled sensory axons and dendrites. Both axons and dendrites degenerate with taxol exposure. Our protocol should facilitate the adoption and expansion of this model to include other neurotoxic compounds.
• Bhattacharya, M. R., Geisler, S., Pittman, S. K., Doan, R. A., Weihl, C. C., Milbrandt, J., & DiAntonio, A. (2016). TMEM184b Promotes Axon Degeneration and Neuromuscular Junction Maintenance. The Journal of neuroscience : the official journal of the Society for Neuroscience, 36(17), 4681-9.
  More info

  Complex nervous systems achieve proper connectivity during development and must maintain these connections throughout life. The processes of axon and synaptic maintenance and axon degeneration after injury are jointly controlled by a number of proteins within neurons, including ubiquitin ligases and mitogen activated protein kinases. However, our understanding of these molecular cascades is incomplete. Here we describe the phenotype resulting from mutation of TMEM184b, a protein identified in a screen for axon degeneration mediators. TMEM184b is highly expressed in the mouse nervous system and is found in recycling endosomes in neuronal cell bodies and axons. Disruption of TMEM184b expression results in prolonged maintenance of peripheral axons following nerve injury, demonstrating a role for TMEM184b in axon degeneration. In contrast to this protective phenotype in axons, uninjured mutant mice have anatomical and functional impairments in the peripheral nervous system. Loss of TMEM184b causes swellings at neuromuscular junctions that become more numerous with age, demonstrating that TMEM184b is critical for the maintenance of synaptic architecture. These swellings contain abnormal multivesicular structures similar to those seen in patients with neurodegenerative disorders. Mutant animals also show abnormal sensory terminal morphology. TMEM184b mutant animals are deficient on the inverted screen test, illustrating a role for TMEM184b in sensory-motor function. Overall, we have identified an important function for TMEM184b in peripheral nerve terminal structure, function, and the axon degeneration pathway.
• Bhattacharya, M. R., Gerdts, J., Naylor, S. A., Royse, E. X., Ebstein, S. Y., Sasaki, Y., Milbrandt, J., & DiAntonio, A. (2012). A model of toxic neuropathy in Drosophila reveals a role for MORN4 in promoting axonal degeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience, 32(15), 5054-61.
  More info

  Axonal degeneration is a molecular self-destruction cascade initiated following traumatic, toxic, and metabolic insults. Its mechanism underlies a number of disorders including hereditary and diabetic neuropathies and the neurotoxic side effects of chemotherapy drugs. Molecules that promote axonal degeneration could represent potential targets for therapy. To identify such molecules, we designed a screening platform based on intoxication of Drosophila larvae with paclitaxel (taxol), a chemotherapeutic agent that causes neuropathy in cancer patients. In Drosophila, taxol treatment causes swelling, fragmentation, and loss of axons in larval peripheral nerves. This axonal loss is not due to apoptosis of neurons. Taxol-induced axonal degeneration in Drosophila shares molecular execution mechanisms with vertebrates, including inhibition by both NMNAT (nicotinamide mononucleotide adenylyltransferase) expression and loss of wallenda/DLK (dual leucine zipper kinase). In a pilot RNAi-based screen we found that knockdown of retinophilin (rtp), which encodes a MORN (membrane occupation and recognition nexus) repeat-containing protein, protects axons from degeneration in the presence of taxol. Loss-of-function mutants of rtp replicate this axonal protection. Knockdown of rtp also delays axonal degeneration in severed olfactory axons. We demonstrate that the mouse ortholog of rtp, MORN4, promotes axonal degeneration in mouse sensory axons following axotomy, illustrating conservation of function. Hence, this new model can identify evolutionarily conserved genes that promote axonal degeneration, and so could identify candidate therapeutic targets for a wide-range of axonopathies.
• Bhattacharya, M. R., Bautista, D. M., Wu, K., Haeberle, H., Lumpkin, E. A., & Julius, D. (2008). Radial stretch reveals distinct populations of mechanosensitive mammalian somatosensory neurons. Proceedings of the National Academy of Sciences of the United States of America, 105(50), 20015-20.
  More info

  Primary afferent somatosensory neurons mediate our sense of touch in response to changes in ambient pressure. Molecules that detect and transduce thermal stimuli have been recently identified, but mechanisms underlying mechanosensation, particularly in vertebrate organisms, remain enigmatic. Traditionally, mechanically evoked responses in somatosensory neurons have been assessed one cell at a time by recording membrane currents in response to application of focal pressure, suction, or osmotic challenge. Here, we used radial stretch in combination with live-cell calcium imaging to gain a broad overview of mechanosensitive neuronal subpopulations. We found that different stretch intensities activate distinct subsets of sensory neurons as defined by size, molecular markers, or pharmacological attributes. In all subsets, stretch-evoked responses required extracellular calcium, indicating that mechanical force triggers calcium influx. This approach extends the repertoire of stimulus paradigms that can be used to examine mechanotransduction in mammalian sensory neurons, facilitating future physiological and pharmacological studies.
• Li, R., Chase, M., Jung, S. K., Smith, P. J., & Loeken, M. R. (2005). Hypoxic stress in diabetic pregnancy contributes to impaired embryo gene expression and defective development by inducing oxidative stress. American Journal of Physiology - Endocrinology and Metabolism, 289(Issue 4). doi:10.1152/ajpendo.00441.2004
  More info

  We have shown that neural tube defects (NTD) in a mouse model of diabetic embryopathy are associated with deficient expression of Pax3, a gene required for neural tube closure. Hyperglycemia-induced oxidative stress is responsible. Before organogenesis, the avascular embryo is physiologically hypoxic (2-5% O2). Here we hypothesized that, because O2 delivery is limited at this stage of development, excess glucose metabolism could accelerate the rate of O2 consumption, thereby exacerbating the hypoxic state. Because hypoxia can increase mitochondrial superoxide production, excessive hypoxia may contribute to oxidative stress. To test this, we assayed O 2 flux, an indicator of O2 availability, in embryos of glucose-injected hyperglycemic or saline-injected mice. O2 flux was reduced by 30% in embryos of hyperglycemic mice. To test whether hypoxia replicates, and hyperoxia suppresses, the effects of maternal hyperglycemia, pregnant mice were housed in controlled O2 chambers on embryonic day 7.5. Housing pregnant mice in 12% O2, or induction of maternal hyperglycemia (>250 mg/dl), decreased Pax3 expression fivefold, and increased NTD eightfold. Conversely, housing pregnant diabetic mice in 30% O2 significantly suppressed the effect of maternal diabetes to increase NTD. These effects of hypoxia appear to be the result of increased production of mitochondrial Superoxide, as indicated by assay of lipid peroxidation, reduced glutathione, and H2O2. Further support of this interpretation was the effect of antioxidants, which blocked the effects of maternal hypoxia, as well as hyperglycemia, on Pax3 expression and NTD. These observations suggest that maternal hyperglycemia depletes O2 in the embryo and that this contributes to oxidative stress and the adverse effects of maternal hyperglycemia on embryo development. Copyright © 2005 the American Physiological Society.
• Li, R., Chase, M., Jung, S. K., Smith, P. J., & Loeken, M. R. (2005). Hypoxic stress in diabetic pregnancy contributes to impaired embryo gene expression and defective development by inducing oxidative stress. American journal of physiology. Endocrinology and metabolism, 289(4), E591-9.
  More info

  We have shown that neural tube defects (NTD) in a mouse model of diabetic embryopathy are associated with deficient expression of Pax3, a gene required for neural tube closure. Hyperglycemia-induced oxidative stress is responsible. Before organogenesis, the avascular embryo is physiologically hypoxic (2-5% O(2)). Here we hypothesized that, because O(2) delivery is limited at this stage of development, excess glucose metabolism could accelerate the rate of O(2) consumption, thereby exacerbating the hypoxic state. Because hypoxia can increase mitochondrial superoxide production, excessive hypoxia may contribute to oxidative stress. To test this, we assayed O(2) flux, an indicator of O(2) availability, in embryos of glucose-injected hyperglycemic or saline-injected mice. O(2) flux was reduced by 30% in embryos of hyperglycemic mice. To test whether hypoxia replicates, and hyperoxia suppresses, the effects of maternal hyperglycemia, pregnant mice were housed in controlled O(2) chambers on embryonic day 7.5. Housing pregnant mice in 12% O(2), or induction of maternal hyperglycemia (>250 mg/dl), decreased Pax3 expression fivefold, and increased NTD eightfold. Conversely, housing pregnant diabetic mice in 30% O(2) significantly suppressed the effect of maternal diabetes to increase NTD. These effects of hypoxia appear to be the result of increased production of mitochondrial superoxide, as indicated by assay of lipid peroxidation, reduced glutathione, and H(2)O(2). Further support of this interpretation was the effect of antioxidants, which blocked the effects of maternal hypoxia, as well as hyperglycemia, on Pax3 expression and NTD. These observations suggest that maternal hyperglycemia depletes O(2) in the embryo and that this contributes to oxidative stress and the adverse effects of maternal hyperglycemia on embryo development.