We are interested in what occurs at a molecular level when neurons are in the earliest stages of neurodegenerative disease. In particular, we study the processes of early axon degeneration and synaptic dysfunction and loss, which occur before neurons die. Molecular pathways activated in these neurons, and their communication with nearby non-neuronal cells, promotes disease progression and ultimately disconnects regions of the brain and peripheral nervous system from one another. We are looking for the earliest events that signal disease states, and hope to find ways to reduce or prevent these processes from occurring.
Our work has extremely broad applications ranging from Chemotherapy-Induced Peripheral Neuropathy (a primarily sensory neuropathy), Amyotrophic Lateral Sclerosis (ALS, a motor neuron disease), spinal cord injury, and diabetic neuropathy, all the way to late-onset CNS dementias including Alzheimer's Disease, Parkinson's Disease, and Frontotemporal Dementia. As such, this work has received funding from numerous public and private sources including cancer research foundations, the Muscular Dystrophy Association, and the NIH/NINDS.
Recent work had led us to investigate the role of the endolysosomal system in the development of both neurodegenerative diseases and neurodevelopmental disorders. Please stay tuned for results in this area!
We take advantage of three systems in the lab: the fruit fly (Drosophila melanogaster) the mouse (Mus musculus), and human iPSC-derived neurons. Each has distinct advantages that enable our multi-system approach to be entirely complementary and will help drive new discoveries. Shown below are terminals of some of our favorite neurons: motor neurons responsible for body movement, and sensory terminals responsible for detecting touch and temperature.
1. What are the roles of TMEM184b in axon degeneration and synapse maintenance? We are using both fly and mouse mutant animals to ask questions about synaptic transmission, axon transport, and autophagy control by the 7-pass transmembrane protein and putatitve GPCR TMEM184b. We are also using transcriptomics and proteomics to investigate TMEM184b pathways.
2. How does the progression of axon degeneration relate to the initiation of pain and numbness in chemotherapy-induced peripheral neuropathy (CIPN)? CIPN is the dose limiting side effect of the cancer treatment drugs paclitaxel (taxol) and vincristine, and this neuropathy causes patients to discontinue their use, limiting the effectiveness of their cancer treatment. We are using behavior and optogenetics to pursue these questions in the fruit fly Drosophila melanogaster and hope to use this knowledge to identify ways to treat painful neuropathy by blocking the underlying dendrite and axon degeneration.
3. How do neurons and non-neuronal cells talk to each other during the early phases of injury? We hope to uncover new signals that enable coordinated regulation of neuronal and glial responses to early disease states.
4. How well does our current knowledge of axon degeneration pathways apply to the early stages of neurodegenerative disorders? It has been suggested based on human neuroimaging that white mater injury is an early event in the pathogenesis of Alzheimer's and Parkinson's disease. We are interested in learning about the earliest steps in synapse loss and nerve injury, and then using this knowledge to improve outcomes for those with diseases ranging from ALS and AD to diabetic neuropathy and lysosomal storage disorders.
5. How do alterations in the endolysosomal system result in a myriad of neurological diseases, some of which occur in childhood while others occur late in life? We are interested in the pathways regulating flux of membrane-bound compartments and organelles in synapses and axons and how these processes contribute to disease.
2025
Chapman, KA*, Ullah F*, Yahiku ZA*…Davis EE, Bhattacharya MRC. (2025) Pathogenic variants in TMEM184B cause a neurodevelopmental syndrome via alteration of metabolic signaling. Accepted August 2025, American Journal of Human Genetics. Preprint version available on medRxiv. DOI: https://doi.org/10.1101/2024.06.27.24309417.
Wright EB, Larsen EG, Padilla-Rodriguez M, Langlais PR, Bhattacharya MRC (2025) Transmembrane protein 184B (TMEM184B) modulates endolysosomal acidification via the vesicular proton pump. J Cell Sci. Link to Paper.
Cimetta AD, Rebecca S. Friesen RS, Davis SM, Bhattacharya, MRC. Neuroscience Vertically Integrated Projects Benefit STEM Student Self-Efficacy and Identity. (2025) SPUR (Scholarship and Practice of Undergraduate Research), May Issue. Link to Article.
This article was featured in a news story by the University of Arizona College of Science!
2023
Wright EB*, Larsen EG*, Coloma-Roessle, C, Hart HR, Bhattacharya MRC. (2023) Transmembrane protein 184B (TMEM184B) promotes expression of synaptic gene networks in the mouse hippocampus. BMC Genomics Sept 20; 84:559. Link to Paper
Bhattacharya MRC (2023). A nerve-wracking buzz: lessons from Drosophila models of peripheral neuropathy and axon degeneration. Front Aging Neurosci Aug 8;15:1166146. Link to Paper
2022
Cho TS*, Beigate E*, Klein NE*, Sweeney ST, Bhattacharya MRC (2022) The putative Drosophila TMEM184B ortholog Tmep ensures proper locomotion by restraining ectopic firing at the neuromuscular junction. Molecular Neurobiology. Link to paper.
This article was featured in a UA News Release, a radio broadcast on KTAR 92.3 Phoenix, and on Arizona Public Media/NPR Science Friday!
Larsen EG, Cho TS, McBride ML, Feng J, Manivannan B, Madura C, Klein NE, Wright EB, Garcia-Verdugo HD, Jarvis C, Khanna R, Hu H, Largent-Milnes TM, Bhattacharya MRC (2022). TMEM184B promotes pruriceptive neuron specification to facilitate itch sensitivity. PAIN. Link to paper.
This article was the Editor's Featured article for this issue, and was featured in a video abstract, which you can watch at this link!
We have also filed a U.S. Patent on using TMEM184B to alleviate itch associated with IL-31 (which happens in eczema and asthma). Looking forward to seeing the impact of our discoveries!
2020
Bhattacharya MRC. (2020) A Chemotherapy-Induced Peripheral Neuropathy Model in Drosophila melanogaster. Methods Mol Biol. 2143:301-310. doi: 10.1007/978-1-0716-0585-1_22. PMID: 32524489
2019 and earlier
Bhattacharya MRC#, Geisler S, Pittman SK, Doan RA, Weihl CC, Milbrandt J, DiAntonio A. TMEM184b Promotes Axon Degeneration and Neuromuscular Junction Maintenance. J Neurosci. 2016 Apr 27;36(17):4681-9. PubMed PMID: 27122027; PubMed Central PMCID: PMC4846669. #Martha is corresponding author as faculty @ STLCOP.
Bhattacharya MR, Gerdts J, Naylor SA, Royse EX, Ebstein SY, Sasaki Y, Milbrandt J, DiAntonio A. A model of toxic neuropathy in Drosophila reveals a role for MORN4 in promoting axonal degeneration. J Neurosci. 2012 Apr 11;32(15):5054-61. PubMed PMID: 22496551; PubMed Central PMCID: PMC3336743.
Bhattacharya MR, Bautista DM, Wu K, Haeberle H, Lumpkin EA, Julius D. Radial stretch reveals distinct populations of mechanosensitive mammalian somatosensory neurons. Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):20015-20. PubMed PMID: 19060212; PubMed Central PMCID: PMC2604979.
Li R, Chase M, Jung SK, Smith PJ, Loeken MR. Hypoxic stress in diabetic pregnancy contributes to impaired embryo gene expression and defective development by inducing oxidative stress. Am J Physiol Endocrinol Metab. 2005 Oct;289(4):E591-9. PubMed PMID: 15928021.