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Zhang L, Jia Z, Wu Q, Bai T, Wang B, Hu X, Li T, Liu X, Fu J, Chen Y, Ding X, Liu Z, Xu Z, Zhou H. Alleviating symptoms of neurodegenerative disorders by astrocyte-specific overexpression of TMEM164 in mice. Nat Metab. 2023 Oct;5(10):1787-1802. Epub 2023 Sep 7 PubMed.
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University of Texas Medical Branch
It’s exciting to see advancements in research that could lead to innovative clinical interventions. This study provides the first evidence of a regulatory role of TMEM164 in astrocyte activation within the nervous system. The study reported that TMEM164 overexpression inhibits the induction of neurotoxic reactive astrocytes and neuronal death in both mouse and human astrocytes, as well as in Alzheimer's and Parkinson's disease mouse models.
The development of an adeno-associated virus (AAV)-mediated strategy for astrocyte-specific overexpression of TMEM164 offers a novel therapeutic target and approach for treating neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. The AAV-mediated strategy efficiently and specifically inhibits the activation of neurotoxic reactive astrocytes in specific brain regions or even throughout the whole brain.
Further research by other researchers is needed to validate these findings. It's also important to fully elucidate the mechanism by which TMEM164 suppresses the release of toxic lipids and its potential as a therapeutic target for neurodegenerative diseases associated with neurotoxic reactive astrocytes.
View all comments by Sagar GaikwadBoston University School of Medicine
Zhang et al. identified one target, human astrocyte-specific protein, TMEM164, which is suppressed in major neurodegenerative diseases including AD, PD, HD, MS, ALS, and FTLD patient brains through unbiased screening of overlapping molecules among these neurodegenerative diseases. This transmembrane protein was revealed as a key regulator in preventing the induction of neurotoxic reactive astrocytes. Overexpression of TMEM164 in neurotoxic brain environment showed decreased glia activation and neuronal death but increased astrocyte phagocytosis and memory function.
Mechanistically, TMEM164 overexpression reduces the neurotoxic saturated lipid synthesis enzyme ELOVL1, potentially through downstream transcription factor CAPN15, resulting in decreased saturated lipids and reduced cell death. While further mechanisms of TMEM164 regulation should be assessed, this study indicates that saturated lipid accumulation discovered in neurodegenerative disease brains, especially AD, could be one of the main causal factors for neuronal death.
Interestingly, six months after delivering astrocyte-targeted, BBB-penetrating AAV-Tmem164 to the mouse AD brain in vivo, astrocyte reactivity was blocked and they showed increased phagocytic, lysosomal, and autophagic profiles. This suggests that Tmem164 may be a key upstream regulator that could maintain the cellular functions of homeostatic and potential astrocyte-targeted therapeutics for common neurodegenerative disease.
While this one target covers six different neurodegenerative diseases, this type of approach can be applied to different neurodegenerative diseases independently in subgroups of patients with different disease status. This would allow us to identify more targets to efficiently prevent neurodegeneration in a particular disease and to understand cell type-specific mechanistic interconnections of targets with disease progression.
View all comments by Julia TCWNYU Langone
This paper by Zhang and colleagues represents a remarkable piece of research that identifies a novel regulator of neurotoxic reactive astrocytes, which are implicated in various neurodegenerative disorders. Here, the authors have discovered that transmembrane protein TMEM164, which is normally expressed in astrocytes, is suppressed by inflammatory cytokines released from activated microglia. TMEM164 acts as a lipid sensor that maintains lipid homeostasis in astrocytes and prevents the accumulation and secretion of saturated lipids that are toxic to neurons. By overexpressing TMEM164 specifically in astrocytes, the authors were able to inhibit the induction of neurotoxic reactive astrocytes and neuronal death. Bravo! These discoveries also provide mechanistic insights into how TMEM164 regulates lipid metabolism and signaling pathways in astrocytes. We had previously discovered microglia-released cytokines that drove neurotoxic reactive astrocyte formation but had not uncovered how astrocyte autonomous factors might be contributing to the transition from physiologically “normal” astrocytes to a pathological reactive subtype.
This paper is significant for several reasons. First, it reveals a previously unknown function of TMEM164 in astrocytes and its role in modulating astrocyte reactivity. Second, it demonstrates that TMEM164 overexpression can effectively protect neurons from neurotoxic reactive astrocytes (by inhibiting both their induction and production of toxic lipids), suggesting a potential therapeutic strategy for neurodegenerative diseases. Third, it sheds light on the molecular mechanisms of astrocyte-neuron interactions and how they are affected by inflammation and lipid dysregulation.
The work of Zhang and colleagues also raises some interesting questions for future research, such as, how is TMEM164 expression regulated by inflammatory signals? Does TMEM164 have other functions in astrocytes or other cell types? And, are other lipid sensors or regulators involved in astrocyte reactivity?
Overall, this paper is an incredibly valuable contribution to the field of glial biology and neurodegeneration. It provides novel insights into the regulation and function of TMEM164 in astrocytes and its impact on neuronal survival. It also offers a promising avenue for developing new interventions to prevent or treat neurodegenerative disorders by targeting astrocyte-specific TMEM164 expression.
View all comments by Shane LiddelowMake a Comment
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