TMBIM6 enhances dopaminergic neuron survival by modulating the IRE1a pathway in Parkinson's disease.

Overview

Authors: Pablo Ahumada-Montalva¹, Francisco Muñoz-Carvajal¹, Sara Bórquez-Macaya¹, Nohela Arévalo-Ramírez¹, Marisol Cisternas-Olmedo^2,3,4, Carolina Jerez^2,3,4, Valentina Urbina-Muñoz^1,2,3,4, Wileidy Gomez^5,6, Pamela J Urrutia^3,7, Etienne C Hirsch⁸, Manuel Ahumada⁹, Pablo Barrias⁹, Camila Muñoz-Yañez⁹, Ariel Herrera-Vásquez¹⁰, Gloria Arriagada¹¹, Ute Woehlbier⁴, Melissa Calegaro-Nassif⁶, Mario Sanhueza¹², Rene L Vidal^2,3,4, Diego Rojas-Rivera¹

ORCID iDs: Francisco Muñoz-Carvajal, Marisol Cisternas-Olmedo, Pamela J Urrutia, Pablo Barrias, Camila Muñoz-Yañez, Ute Woehlbier, Melissa Calegaro-Nassif, Mario Sanhueza, Diego Rojas-Rivera

Institutions: Universidad Mayor (Chile); The University of Texas Health Science Center at Houston (United States); University of Chile (Chile); Sorbonne Université (France); Institut du Cerveau (France); Universidad Andrés Bello (Chile)

Journal: Cell death & disease, volume 17, issue 1, article 385

Dates: received 30 April 2025; accepted 15 December 2025; published online 3 April 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1038/s41419-025-08391-5 · PMID 41932887 · PMCID PMC13061952 · OpenAlex W7148631028

Open access: gold, a free copy (OpenAlex)

Status: data only

Categories: human (organism), mouse (organism), Parkinson's (population), cellular / molecular (subfield)

Methods: Statistics, Preprocessing, Evoked potentials, Connectivity, Machine learning

Keywords: Apoptosis, Parkinson's disease, Mechanisms of disease, Cell death in the nervous system, Neurodegeneration

MeSH: Dopaminergic Neurons*, Endoribonucleases*, Membrane Proteins*, Parkinson Disease*, Protein Serine-Threonine Kinases*, alpha-Synuclein, Animals, Cell Survival, Endoplasmic Reticulum Chaperone BiP, Endoplasmic Reticulum Stress, Humans, Male, Mice, Mice, Inbred C57BL, Oxidopamine, Rotenone, Signal Transduction, Unfolded Protein Response (* major topic)

Topic: Endoplasmic Reticulum Stress and Disease (Cell Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex

Funding: Agence Nationale de la Recherche (ANR-10-IAIHU06, 10-IAIHU-06, ANR-10); International Brain Research Organization (IBRO); Institut National de la Santé et de la Recherche Médicale (ANR-10-IAIHU-06); Centre National de la Recherche Scientifique; Agencia Nacional de Investigación y Desarrollo (1220480, 1240176, 3250688, 11180546, 3240455, 1241229, ID24I10049, 1240785, 1230823, FONDECYT 1240785, 1230980); Fondo de Fomento al Desarrollo Científico y Tecnológico (1241229)

Citations: cited by 2 papers (Europe PMC); 72 references in the paper

Abstract

The core pathological hallmark of Parkinson’s disease (PD) is the progressive degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), driven by misfolding and aggregation of a-synuclein (aSyn) into Lewy bodies. This triggers severe cellular dysfunction, including endoplasmic reticulum (ER) stress and the dysregulation of the unfolded protein response (UPR). TMBIM6, an anti-apoptotic ER protein, inhibits the UPR sensor IRE1a. Although TMBIM6 exhibits neuroprotective effects in neurological disorders, its role in PD-related DAergic neuron survival remains unknown. We report that TMBIM6 mRNA is increased in cellular models exposed to 6-hydroxydopamine (6-OHDA), rotenone, or aSyn preformed fibrils (PFFs), whereas TMBIM6 protein levels are elevated in postmortem PD SNpc, indicating translational relevance. Modulating TMBIM6 expression in DAergic cells and primary neurons showed that knockdown increased aSyn toxicity, while overexpression is protective. Single-cell RNA-seq analysis of PD SN revealed selective disruption of TMBIM6 co-expression with key UPR effectors (HSPA5, ERN1, and XBP1), and reduced TMBIM6 levels in vulnerable DAergic neurons. Mechanistically, TMBIM6 directly binds IRE1a, and aSyn PFFs disrupt this complex, leading to IRE1a activation; genetic or pharmacological IRE1a inhibition prevented cell death in TMBIM6-deficient cells. In vivo, TMBIM6 downregulation in Drosophila melanogaster worsens rotenone-induced DAergic neuron degeneration and motor impairments, while adeno-associated virus (AAV)-mediated TMBIM6 overexpression in mice improves motor function and neuron survival. Our results demonstrate that TMBIM6 modulates ER stress responses, promoting DAergic neuron survival by regulating IRE1a activity. Consequently, the TMBIM6/IRE1a axis represents a promising therapeutic target for mitigating neurodegeneration in PD and related disorders.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

geo:GSE8397, at NCBI GEO; found in the text, “In silico TMBIM6 expression analysis”

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

Funding: added Agence Nationale de la Recherche: ANR-10-IAIHU06, 10-IAIHU-06, ANR-10; International Brain Research Organization; Institut National de la Santé et de la Recherche Médicale: ANR-10-IAIHU-06; Centre National de la Recherche Scientifique; Agencia Nacional de Investigación y Desarrollo: 1220480, 1240176, 3250688, 11180546, 3240455, 1241229, ID24I10049, 1240785, 1230823, FONDECYT 1240785, 1230980; Fondo de Fomento al Desarrollo Científico y Tecnológico: 1241229

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 20 authors, 5 keywords, 18 MeSH terms, 72 references.

Cite

This paper

Ahumada-Montalva, P., Muñoz-Carvajal, F., Bórquez-Macaya, S., Arévalo-Ramírez, N., Cisternas-Olmedo, M., Jerez, C., Urbina-Muñoz, V., Gomez, W., Urrutia, P. J., Hirsch, E. C., Ahumada, M., Barrias, P., Muñoz-Yañez, C., Herrera-Vásquez, A., Arriagada, G., Woehlbier, U., Calegaro-Nassif, M., Sanhueza, M., Vidal, R. L., & Rojas-Rivera, D. (2026). TMBIM6 enhances dopaminergic neuron survival by modulating the IRE1a pathway in Parkinson's disease. Cell death & disease, 17(1), 385. https://doi.org/10.1038/s41419-025-08391-5

BibTeX

@article{ahumadamontalva2026tmbim6, author = {Ahumada-Montalva, Pablo and Muñoz-Carvajal, Francisco and Bórquez-Macaya, Sara and Arévalo-Ramírez, Nohela and Cisternas-Olmedo, Marisol and Jerez, Carolina and Urbina-Muñoz, Valentina and Gomez, Wileidy and Urrutia, Pamela J and Hirsch, Etienne C and Ahumada, Manuel and Barrias, Pablo and Muñoz-Yañez, Camila and Herrera-Vásquez, Ariel and Arriagada, Gloria and Woehlbier, Ute and Calegaro-Nassif, Melissa and Sanhueza, Mario and Vidal, Rene L and Rojas-Rivera, Diego}, title = {{TMBIM6 enhances dopaminergic neuron survival by modulating the IRE1a pathway in Parkinson's disease}}, journal = {Cell death \& disease}, year = {2026}, month = apr, volume = {17}, number = {1}, pages = {385}, publisher = {Nature Publishing Group}, issn = {2041-4889}, doi = {10.1038/s41419-025-08391-5}, url = {https://doi.org/10.1038/s41419-025-08391-5}, pmid = {41932887}, pmcid = {PMC13061952} }

RIS

TY - JOUR AU - Ahumada-Montalva, Pablo AU - Muñoz-Carvajal, Francisco AU - Bórquez-Macaya, Sara AU - Arévalo-Ramírez, Nohela AU - Cisternas-Olmedo, Marisol AU - Jerez, Carolina AU - Urbina-Muñoz, Valentina AU - Gomez, Wileidy AU - Urrutia, Pamela J AU - Hirsch, Etienne C AU - Ahumada, Manuel AU - Barrias, Pablo AU - Muñoz-Yañez, Camila AU - Herrera-Vásquez, Ariel AU - Arriagada, Gloria AU - Woehlbier, Ute AU - Calegaro-Nassif, Melissa AU - Sanhueza, Mario AU - Vidal, Rene L AU - Rojas-Rivera, Diego TI - TMBIM6 enhances dopaminergic neuron survival by modulating the IRE1a pathway in Parkinson's disease T2 - Cell death & disease J2 - Cell Death Dis PY - 2026 DA - 2026/04/03 VL - 17 IS - 1 SP - 385 SN - 2041-4889 PB - Nature Publishing Group DO - 10.1038/s41419-025-08391-5 UR - https://doi.org/10.1038/s41419-025-08391-5 LA - en ER -

CSL-JSON

{ "id": "10.1038/s41419-025-08391-5", "type": "article-journal", "title": "TMBIM6 enhances dopaminergic neuron survival by modulating the IRE1a pathway in Parkinson's disease", "container-title": "Cell death & disease", "author": [ { "family": "Ahumada-Montalva", "given": "Pablo" }, { "family": "Muñoz-Carvajal", "given": "Francisco" }, { "family": "Bórquez-Macaya", "given": "Sara" }, { "family": "Arévalo-Ramírez", "given": "Nohela" }, { "family": "Cisternas-Olmedo", "given": "Marisol" }, { "family": "Jerez", "given": "Carolina" }, { "family": "Urbina-Muñoz", "given": "Valentina" }, { "family": "Gomez", "given": "Wileidy" }, { "family": "Urrutia", "given": "Pamela J" }, { "family": "Hirsch", "given": "Etienne C" }, { "family": "Ahumada", "given": "Manuel" }, { "family": "Barrias", "given": "Pablo" }, { "family": "Muñoz-Yañez", "given": "Camila" }, { "family": "Herrera-Vásquez", "given": "Ariel" }, { "family": "Arriagada", "given": "Gloria" }, { "family": "Woehlbier", "given": "Ute" }, { "family": "Calegaro-Nassif", "given": "Melissa" }, { "family": "Sanhueza", "given": "Mario" }, { "family": "Vidal", "given": "Rene L" }, { "family": "Rojas-Rivera", "given": "Diego" } ], "container-title-short": "Cell Death Dis", "volume": "17", "issue": "1", "page": "385", "DOI": "10.1038/s41419-025-08391-5", "PMID": "41932887", "PMCID": "PMC13061952", "ISSN": "2041-4889", "publisher": "Nature Publishing Group", "URL": "https://doi.org/10.1038/s41419-025-08391-5", "language": "en", "issued": { "date-parts": [ [ 2026, 4, 3 ] ] } }

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Sign in with ORCID to claim this paper as one of its authors, correct its record or validate its tracing map: when the paper's metadata lists your ORCID iD, you are recognized at once. Maintainers of its code: sign in with GitHub, then claim the repository on your account page.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion, reproductions, activity

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.