bims-nenemi 2023-09-24 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2023–09–24
fourteen papers selected by
Marco Tigano, Thomas Jefferson University

The cGAS-STING pathway-dependent sensing of mitochondrial DNA mediates ocular surface inflammation.
Temporal landscape of mitochondrial proteostasis governed by the UPRmt.
Molecular basis for maternal inheritance of human mitochondrial DNA.
Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.
Manipulating mitochondrial electron flow enhances tumor immunogenicity.
Oxidative stress induces mitochondrial iron overload and ferroptotic cell death.
The mitoepigenome responds to stress, suggesting novel mito-nuclear interactions in vertebrates.
KAT2 paralogs prevent dsRNA accumulation and interferon signaling to maintain intestinal stem cells.
Metabolic control of antitumor immunity.
Atypical peripheral actin band formation via overactivation of RhoA and Non-muscle myosin II in Mitofusin 2 deficient cells.
Role of cGAS-STING signaling pathway in cardiometabolic diseases.
Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8+ T cell metabolic fitness and function in tumors.
Recessive MECR pathogenic variants cause an LHON-like optic neuropathy.
C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9.

Signal Transduct Target Ther. 2023 Sep 21. 8(1): 371

The cGAS-STING pathway-dependent sensing of mitochondrial DNA mediates ocular surface inflammation.

Weijie Ouyang, Shoubi Wang, Dan Yan, Jieli Wu, Yunuo Zhang, Wei Li, Jiaoyue Hu, Zuguo Liu.

The innate immune response is the main pathophysiological process of ocular surface diseases exposed to multiple environmental stresses. The epithelium is central to the innate immune response, but whether and how innate immunity is initiated by ocular epithelial cells in response to various environmental stresses in ocular surface diseases, such as dry eye, is still unclear. By utilizing two classic experimental dry eye models-a mouse ocular surface treated with benzalkonium chloride (BAC) and a mouse model with surgically removed extraorbital lachrymal glands, as well as dry eye patient samples-along with human corneal epithelial cells (HCE) exposed to hyperosmolarity, we have discovered a novel innate immune pathway in ocular surface epithelial cells. Under stress, mitochondrial DNA (mtDNA) was released into the cytoplasm through the mitochondrial permeability transition pore (mPTP) and further activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, aggravating downstream inflammatory responses and ocular surface damage. Genetic deletion or pharmacological suppression of STING and inhibition of mtDNA release reduced inflammatory responses, whereas mtDNA transfection supported cytoplasmic mtDNA-induced inflammatory responses by activating the cGAS-STING pathway. Our study clarified the cGAS-STING pathway-dependent sensing of mitochondrial DNA-mediated ocular surface inflammation, which elucidated a new mechanism of ocular surface diseases in response to multiple environmental stresses.

DOI: https://doi.org/10.1038/s41392-023-01624-z
Sci Adv. 2023 Sep 22. 9(38): eadh8228

Temporal landscape of mitochondrial proteostasis governed by the UPRmt.

Louise Uoselis, Runa Lindblom, Wai Kit Lam, Catharina J Küng, Marvin Skulsuppaisarn, Grace Khuu, Thanh N Nguyen, Danielle L Rudler, Aleksandra Filipovska, Ralf B Schittenhelm, Michael Lazarou.

Breakdown of mitochondrial proteostasis activates quality control pathways including the mitochondrial unfolded protein response (UPRmt) and PINK1/Parkin mitophagy. However, beyond the up-regulation of chaperones and proteases, we have a limited understanding of how the UPRmt remodels and restores damaged mitochondrial proteomes. Here, we have developed a functional proteomics framework, termed MitoPQ (Mitochondrial Proteostasis Quantification), to dissect the UPRmt's role in maintaining proteostasis during stress. We find essential roles for the UPRmt in both protecting and repairing proteostasis, with oxidative phosphorylation metabolism being a central target of the UPRmt. Transcriptome analyses together with MitoPQ reveal that UPRmt transcription factors drive independent signaling arms that act in concert to maintain proteostasis. Unidirectional interplay between the UPRmt and PINK1/Parkin mitophagy was found to promote oxidative phosphorylation recovery when the UPRmt failed. Collectively, this study defines the network of proteostasis mediated by the UPRmt and highlights the value of functional proteomics in decoding stressed proteomes.

DOI: https://doi.org/10.1126/sciadv.adh8228
Nat Genet. 2023 Sep 18.

Molecular basis for maternal inheritance of human mitochondrial DNA.

William Lee, Angelica Zamudio-Ochoa, Gina Buchel, Petar Podlesniy, Nuria Marti Gutierrez, Margalida Puigròs, Anna Calderon, Hsin-Yao Tang, Li Li, Aleksei Mikhalchenko, Amy Koski, Ramon Trullas, Shoukhrat Mitalipov, Dmitry Temiakov.

Uniparental inheritance of mitochondrial DNA (mtDNA) is an evolutionary trait found in nearly all eukaryotes. In many species, including humans, the sperm mitochondria are introduced to the oocyte during fertilization1,2. The mechanisms hypothesized to prevent paternal mtDNA transmission include ubiquitination of the sperm mitochondria and mitophagy3,4. However, the causative mechanisms of paternal mtDNA elimination have not been defined5,6. We found that mitochondria in human spermatozoa are devoid of intact mtDNA and lack mitochondrial transcription factor A (TFAM)-the major nucleoid protein required to protect, maintain and transcribe mtDNA. During spermatogenesis, sperm cells express an isoform of TFAM, which retains the mitochondrial presequence, ordinarily removed upon mitochondrial import. Phosphorylation of this presequence prevents mitochondrial import and directs TFAM to the spermatozoon nucleus. TFAM relocalization from the mitochondria of spermatogonia to the spermatozoa nucleus directly correlates with the elimination of mtDNA, thereby explaining maternal inheritance in this species.

DOI: https://doi.org/10.1038/s41588-023-01505-9
bioRxiv. 2023 Sep 05. pii: 2023.09.01.555986. [Epub ahead of print]

Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.

Spencer D Shelton, Sara House, Vijayashree Ramesh, Zhenkang Chen, Tao Wei, Xun Wang, Claire B Llamas, Siva Sai Krishna Venigalla, Cameron J Menezes, Zhiyu Zhao, Jennifer G Gill, Ralph J DeBerardinis, Sean J Morrison, Alpaslan Tasdogan, Prashant Mishra.

Mitochondrial DNA (mtDNA) mutations are frequently observed in cancer, but their contribution to tumor progression is controversial. To evaluate the impact of mtDNA variants on tumor growth and metastasis, we created human melanoma cytoplasmic hybrid (cybrid) cell lines transplanted with wildtype mtDNA or pathogenic mtDNA encoding variants that partially or completely inhibit oxidative phosphorylation. Homoplasmic pathogenic mtDNA cybrids reliably established tumors despite dysfunctional oxidative phosphorylation. However, pathogenic mtDNA variants disrupted spontaneous metastasis of subcutaneous tumors and decreased the abundance of circulating melanoma cells in the blood. Pathogenic mtDNA did not induce anoikis or inhibit organ colonization of melanoma cells following intravenous injections. Instead, migration and invasion were reduced, indicating that limited circulation entry functions as a metastatic bottleneck amidst mtDNA dysfunction. Furthermore, analysis of selective pressure exerted on the mitochondrial genomes of heteroplasmic cybrid lines revealed a suppression of pathogenic mtDNA allelic frequency during melanoma growth. Collectively, these findings demonstrate that functional mtDNA is favored during melanoma growth and enables metastatic entry into the blood.

DOI: https://doi.org/10.1101/2023.09.01.555986
Science. 2023 Sep 22. 381(6664): 1316-1323

Manipulating mitochondrial electron flow enhances tumor immunogenicity.

Kailash Chandra Mangalhara, Siva Karthik Varanasi, Melissa A Johnson, Mannix J Burns, Gladys R Rojas, Pau B Esparza Moltó, Alva G Sainz, Nimesha Tadepalle, Keene L Abbott, Gaurav Mendiratta, Dan Chen, Yagmur Farsakoglu, Tenzin Kunchok, Filipe Araujo Hoffmann, Bianca Parisi, Mercedes Rincon, Matthew G Vander Heiden, Marcus Bosenberg, Diana C Hargreaves, Susan M Kaech, Gerald S Shadel.

Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.

DOI: https://doi.org/10.1126/science.abq1053
Sci Rep. 2023 Sep 19. 13(1): 15515

Oxidative stress induces mitochondrial iron overload and ferroptotic cell death.

Yi Chen, Xiaoyun Guo, Yachang Zeng, Xiaoliang Mo, Siqi Hong, Hui He, Jing Li, Sulail Fatima, Qinghang Liu.

Oxidative stress has been shown to induce cell death in a wide range of human diseases including cardiac ischemia/reperfusion injury, drug induced cardiotoxicity, and heart failure. However, the mechanism of cell death induced by oxidative stress remains incompletely understood. Here we provide new evidence that oxidative stress primarily induces ferroptosis, but not apoptosis, necroptosis, or mitochondria-mediated necrosis, in cardiomyocytes. Intriguingly, oxidative stress induced by organic oxidants such as tert-butyl hydroperoxide (tBHP) and cumene hydroperoxide (CHP), but not hydrogen peroxide (H2O2), promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to increased lipid peroxidation. Moreover, elevated oxidative stress is also linked to labile iron overload through downregulation of the transcription suppressor BTB and CNC homology 1 (Bach1), upregulation of heme oxygenase 1 (HO-1) expression, and enhanced iron release via heme degradation. Strikingly, oxidative stress also promoted HO-1 translocation to mitochondria, leading to mitochondrial iron overload and lipid reactive oxygen species (ROS) accumulation. Targeted inhibition of mitochondrial iron overload or ROS accumulation, by overexpressing mitochondrial ferritin (FTMT) or mitochondrial catalase (mCAT), respectively, markedly inhibited oxidative stress-induced ferroptosis. The levels of mitochondrial iron and lipid peroxides were also markedly increased in cardiomyocytes subjected to simulated ischemia and reperfusion (sI/R) or the chemotherapeutic agent doxorubicin (DOX). Overexpressing FTMT or mCAT effectively prevented cardiomyocyte death induced by sI/R or DOX. Taken together, oxidative stress induced by organic oxidants but not H2O2 primarily triggers ferroptotic cell death in cardiomyocyte through GPX4 and Bach1/HO-1 dependent mechanisms. Our results also reveal mitochondrial iron overload via HO-1 mitochondrial translocation as a key mechanism as well as a potential molecular target for oxidative stress-induced ferroptosis in cardiomyocytes.

DOI: https://doi.org/10.1038/s41598-023-42760-4
BMC Genomics. 2023 Sep 22. 24(1): 561

The mitoepigenome responds to stress, suggesting novel mito-nuclear interactions in vertebrates.

John Lees, Fábio Pèrtille, Pia Løtvedt, Per Jensen, Carlos Guerrero Bosagna.

  The mitochondria are central in the cellular response to changing environmental conditions resulting from disease states, environmental exposures or normal physiological processes. Although the influences of environmental stressors upon the nuclear epigenome are well characterized, the existence and role of the mitochondrial epigenome remains contentious. Here, by quantifying the mitochondrial epigenomic response of pineal gland cells to circadian stress, we confirm the presence of extensive cytosine methylation within the mitochondrial genome. Furthermore, we identify distinct epigenetically plastic regions (mtDMRs) which vary in cytosinic methylation, primarily in a non CpG context, in response to stress and in a sex-specific manner. Motifs enriched in mtDMRs contain recognition sites for nuclear-derived DNA-binding factors (ATF4, HNF4A) important in the cellular metabolic stress response, which we found to be conserved across diverse vertebrate taxa. Together, these findings suggest a new layer of mito-nuclear interaction in which the nuclear metabolic stress response could alter mitochondrial transcriptional dynamics through the binding of nuclear-derived transcription factors in a methylation-dependent context.

Keywords:  DNA-binding; Epigenome; Methylation; Mitochondrial genome; Pineal gland

DOI:  https://doi.org/10.1186/s12864-023-09668-9
bioRxiv. 2023 Sep 05. pii: 2023.09.04.556156. [Epub ahead of print]

KAT2 paralogs prevent dsRNA accumulation and interferon signaling to maintain intestinal stem cells.

Mai-Uyen Nguyen, Sarah Potgieter, Winston Huang, Julie Pfeffer, Sean Woo, Caifeng Zhao, Matthew Lawlor, Richard Yang, Angela Halstead, Sharon Dent, José B Sáenz, Haiyan Zheng, Zuo-Fei Yuan, Simone Sidoli, Christopher E Ellison, Michael Verzi.

Histone acetyltransferases KAT2A and KAT2B are paralogs highly expressed in the intestinal epithelium, but their functions are not well understood. In this study, double knockout of murine Kat2 genes in the intestinal epithelium was lethal, resulting in robust activation of interferon signaling and interferon-associated phenotypes including the loss of intestinal stem cells. Use of pharmacological agents and sterile organoid cultures indicated a cell-intrinsic double-stranded RNA trigger for interferon signaling. Acetyl-proteomics and dsRIP-seq were employed to interrogate the mechanism behind this response, which identified mitochondria-encoded double-stranded RNA as the source of intrinsic interferon signaling. Kat2a and Kat2b therefore play an essential role in regulating mitochondrial functions as well as maintaining intestinal health.
Highlights of the work: Kat2a and Kat2b double knockout in the murine intestinal epithelium triggers activation of the interferon signaling pathway Kat2a/Kat2b knockout leads to intestinal stem cell loss and other mucosal phenotypes consistent with interferon activation Histone PTM mass spec profiling reveals the first in vivo study showing H3K9ac-specific loss with Kat2a and Kat2b double knockout, yet without correlation to interferon signaling pathway genes Comprehensive proteomic analysis identifies non-histone acetyl-lysine targets of KAT2 in the mouse intestine in vivo, including mitochondrial proteins Mitochondrial function is compromised upon Kat2 loss dsRIP-seq identifies double-stranded RNA from the mitochondria as a trigger for the intrinsic immune response upon Kat2 double knockout.

DOI: https://doi.org/10.1101/2023.09.04.556156
Science. 2023 Sep 22. 381(6664): 1287-1288

Metabolic control of antitumor immunity.

Andromachi Pouikli, Christian Frezza.

Mitochondrial metabolite reduces melanoma growth by boosting antigen presentation.

DOI: https://doi.org/10.1126/science.adk1785
Elife. 2023 Sep 19. pii: e88828. [Epub ahead of print]12

Atypical peripheral actin band formation via overactivation of RhoA and Non-muscle myosin II in Mitofusin 2 deficient cells.

Yueyang Wang, Lee D Troughton, Fan Xu, Aritra Chatterjee, Chang Ding, Han Zhao, Laura P Cifuentes, Ryan B Wagner, Tianqi Wang, Shelly Tan, Jingjuan Chen, Linlin Li, David Umulis, Shihuan Kuang, Daniel M Suter, Chongli Yuan, Deva Chan, Fang Huang, Patrick W Oakes, Qing Deng.

  Cell spreading and migration play central roles in many physiological and pathophysiological processes. We have previously shown that MFN2 regulates the migration of human neutrophil-like cells via suppressing Rac activation. Here, we show that in mouse embryonic fibroblasts, MFN2 suppresses RhoA activation and supports cell polarization. After initial spreading, the wild-type cells polarize and migrate, whereas the Mfn2-/- cells maintain a circular shape. Increased cytosolic Ca2+ resulting from the loss of Mfn2 is directly responsible for this phenotype, which can be rescued by expressing an artificial tether to bring mitochondria and ER to close vicinity. Elevated cytosolic Ca2+ activates Ca2+/calmodulin-dependent protein kinase II, RhoA, and Myosin light-chain kinase, causing an over-activation of non-muscle Myosin II, leading to a formation of a prominent F-actin ring at the cell periphery and increased cell contractility. The peripheral actin band alters cell physics and is dependent on substrate rigidity. Our results provide a novel molecular basis to understand how MFN2 regulates distinct signaling pathways in different cells and tissue environments, which is instrumental in understanding and treating MFN2-related diseases.

Keywords:  cell biology; none

DOI:  https://doi.org/10.7554/eLife.88828
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2023 Jul 28. pii: 1672-7347(2023)07-1086-12. [Epub ahead of print]48(7): 1086-1097

Role of cGAS-STING signaling pathway in cardiometabolic diseases.

Huiqing Ding, Yuying Zhou, Zhiyi Yin, Shi Tai.

  Cardiometabolic disease is a common clinical syndrome with exact causal relationship between the aberrant of glucose/lipid metabolism and cardiovascular disfunction, but its pathogenesis is unclear. Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon gene (STING) signaling pathway regulates the activation of innate immunity by sensing intracellular double stranded DNA. Metabolic risk factors drive the activation of cGAS-STING pathway through mitochondrial DNA, nuclear DNA and endoplasmic reticulum stress. In addition, the activation of the cGAS-STING pathway triggers chronic sterile inflammation, excessive activation of autophagy, senescence and apoptosis in related cells of cardiovascular system. These changes induced by cGAS-STING pathway might be implicated in the onset and deterioration of cardiometabolic disease. Therefore, the targeting intervention of cGAS-STING signaling pathway may emerge as a novel treatment for cardiometabolic disease.

Keywords:  autophagy; cardiometabolic disease; cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon gene signaling pathway; senescence

DOI:  https://doi.org/10.11817/j.issn.1672-7347.2023.230028
Sci Immunol. 2023 Sep 29. 8(87): eabq2424

Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8+ T cell metabolic fitness and function in tumors.

Jie-Feng Yang, Xudong Xing, Li Luo, Xin-Wei Zhou, Jian-Xiong Feng, Kang-Bo Huang, Huashan Liu, Shanzhao Jin, Yi-Na Liu, Shi-Hui Zhang, Yi-Hui Pan, Bing Yu, Jin-Yu Yang, Yu-Lu Cao, Yun Cao, Cliff Y Yang, Yuan Wang, Yuxia Zhang, Jiang Li, Xiaojun Xia, Tiebang Kang, Rui-Hua Xu, Ping Lan, Jun-Hang Luo, Hui Han, Fan Bai, Song Gao.

Metabolic fitness of T cells is essential for their vitality, which is largely dependent on the behavior of the mitochondria. The nature of mitochondrial behavior in tumor-infiltrating T cells remains poorly understood. In this study, we show that mitofusin-2 (MFN2) expression is positively correlated with the prognosis of multiple cancers. Genetic ablation of Mfn2 in CD8+ T cells dampens mitochondrial metabolism and function and promotes tumor progression. In tumor-infiltrating CD8+ T cells, MFN2 enhances mitochondria-endoplasmic reticulum (ER) contact by interacting with ER-embedded Ca2+-ATPase SERCA2, facilitating the mitochondrial Ca2+ influx required for efficient mitochondrial metabolism. MFN2 stimulates the ER Ca2+ retrieval activity of SERCA2, thereby preventing excessive mitochondrial Ca2+ accumulation and apoptosis. Elevating mitochondria-ER contact by increasing MFN2 in CD8+ T cells improves the efficacy of cancer immunotherapy. Thus, we reveal a tethering-and-buffering mechanism of organelle cross-talk that regulates the metabolic fitness of tumor-infiltrating CD8+ T cells and highlights the therapeutic potential of enhancing MFN2 expression to optimize T cell function.

DOI: https://doi.org/10.1126/sciimmunol.abq2424
J Med Genet. 2023 Sep 21. pii: jmg-2023-109340. [Epub ahead of print]

Recessive MECR pathogenic variants cause an LHON-like optic neuropathy.

Claudio Fiorini, Andrea Degiorgi, Maria Lucia Cascavilla, Concetta Valentina Tropeano, Chiara La Morgia, Marco Battista, Danara Ormanbekova, Flavia Palombo, Michele Carbonelli, Francesco Bandello, Valerio Carelli, Alessandra Maresca, Piero Barboni, Enrico Baruffini, Leonardo Caporali.

   BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder characterised by complex I defect leading to sudden degeneration of retinal ganglion cells. Although typically associated with pathogenic variants in mitochondrial DNA, LHON was recently described in patients carrying biallelic variants in nuclear genes DNAJC30, NDUFS2 and MCAT. MCAT is part of mitochondrial fatty acid synthesis (mtFAS), as also MECR, the mitochondrial trans-2-enoyl-CoA reductase. MECR mutations lead to a recessive childhood-onset syndromic disorder with dystonia, optic atrophy and basal ganglia abnormalities.
METHODS: We studied through whole exome sequencing two sisters affected by sudden and painless visual loss at young age, with partial recovery and persistent central scotoma. We modelled the candidate variant in yeast and studied mitochondrial dysfunction in yeast and fibroblasts. We tested protein lipoylation and cell response to oxidative stress in yeast.
RESULTS: Both sisters carried a homozygous pathogenic variant in MECR (p.Arg258Trp). In yeast, the MECR-R258W mutant showed an impaired oxidative growth, 30% reduction in oxygen consumption rate and 80% decrease in protein levels, pointing to structure destabilisation. Fibroblasts confirmed the reduced amount of MECR protein, but failed to reproduce the OXPHOS defect. Respiratory complexes assembly was normal. Finally, the yeast mutant lacked lipoylation of key metabolic enzymes and was more sensitive to H2O2 treatment. Lipoic Acid supplementation partially rescued the growth defect.
CONCLUSION: We report the first family with homozygous MECR variant causing an LHON-like optic neuropathy, which pairs the recent MCAT findings, reinforcing the impairment of mtFAS as novel pathogenic mechanism in LHON.

Keywords:  Genetics, Medical; Neuromuscular Diseases; Ophthalmology

DOI:  https://doi.org/10.1136/jmg-2023-109340
Nat Commun. 2023 Sep 22. 14(1): 5898

C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9.

Björn F Vahsen, Sumedha Nalluru, Georgia R Morgan, Lucy Farrimond, Emily Carroll, Yinyan Xu, Kaitlyn M L Cramb, Benazir Amein, Jakub Scaber, Antigoni Katsikoudi, Ana Candalija, Mireia Carcolé, Ruxandra Dafinca, Adrian M Isaacs, Richard Wade-Martins, Elizabeth Gray, Martin R Turner, Sally A Cowley, Kevin Talbot.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, with additional pathophysiological involvement of non-neuronal cells such as microglia. The commonest ALS-associated genetic variant is a hexanucleotide repeat expansion (HRE) mutation in C9orf72. Here, we study its consequences for microglial function using human iPSC-derived microglia. By RNA-sequencing, we identify enrichment of pathways associated with immune cell activation and cyto-/chemokines in C9orf72 HRE mutant microglia versus healthy controls, most prominently after LPS priming. Specifically, LPS-primed C9orf72 HRE mutant microglia show consistently increased expression and release of matrix metalloproteinase-9 (MMP9). LPS-primed C9orf72 HRE mutant microglia are toxic to co-cultured healthy motor neurons, which is ameliorated by concomitant application of an MMP9 inhibitor. Finally, we identify release of dipeptidyl peptidase-4 (DPP4) as a marker for MMP9-dependent microglial dysregulation in co-culture. These results demonstrate cellular dysfunction of C9orf72 HRE mutant microglia, and a non-cell-autonomous role in driving C9orf72-ALS pathophysiology in motor neurons through MMP9 signaling.

DOI: https://doi.org/10.1038/s41467-023-41603-0