دورية أكاديمية
Depletion of TDP-43 exacerbates tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-mediated endoproteolysis of tau in a mouse model of Multiple Etiology Dementia.
| العنوان: | Depletion of TDP-43 exacerbates tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-mediated endoproteolysis of tau in a mouse model of Multiple Etiology Dementia. |
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| المؤلفون: | Baghel MS; Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205, USA., Burns GD; Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205, USA., Tsapatsis M; Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205, USA., Mallika AP; Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205, USA., Cruz ALF; Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205, USA., Cao T; Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205, USA., Chen XK; Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205, USA., Rosa I; Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205, USA., Marx SR; Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205, USA., Ye Y; Department of Physiology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205, USA., Sun S; Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205, USA.; Department of Physiology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205, USA.; Department of Neuroscience, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205, USA., Li T; Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205, USA., Wong PC; Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205, USA.; Department of Neuroscience, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205, USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 29. Date of Electronic Publication: 2024 Jun 29. |
| نوع المنشور: | Journal Article; Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | TDP-43 proteinopathy, initially disclosed in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coexists with tauopathy in a variety of neurodegenerative disorders, termed multiple etiology dementias (MEDs), including Alzheimer's Disease (AD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration and steeper cognitive decline, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. The loss of TDP-43 splicing repression that occurs in presymptomatic ALS-FTD individuals suggests that such early loss could facilitate the pathological conversion of tau to accelerate neuron loss. Here, we report that the loss of TDP-43 repression of cryptic exons in forebrain neurons ( CaMKII-CreER;Tardbp f/f mice) is necessary to exacerbate tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-dependent cleavage of endogenous tau to promote tauopathy. Corroborating this finding within the human context, we demonstrate that loss of TDP-43 function in iPSC-derived cortical neurons promotes early cryptic exon inclusion and subsequent caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in CaMKII-CreER;Tardbp f/f mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed positively correlates with levels of caspase 3-cleaved tau. Importantly, we found that the vulnerability of hippocampal neurons to TDP-43 depletion is dependent on the amount of caspase 3-cleaved tau: from most vulnerable neurons in the CA2/3, followed by those in the dentate gyrus, to the least in CA1. Taken together, our findings strongly support the view that TDP-43 loss-of-function exacerbates tauopathy-dependent brain atrophy by increasing the sensitivity of vulnerable neurons to caspase 3-mediated endoproteolysis of tau, resulting in a greater degree of neurodegeneration in human disorders with co-pathologies of tau and TDP-43. Our work thus discloses novel mechanistic insights and therapeutic targets for human tauopathies harboring co-pathology of TDP-43 and provides a new MED model for testing therapeutic strategies. |
| معلومات مُعتمدة: | R01 NS095969 United States NS NINDS NIH HHS; R61 NS115161 United States NS NINDS NIH HHS; F31 NS135935 United States NS NINDS NIH HHS; R33 NS115161 United States NS NINDS NIH HHS; RF1 NS127925 United States NS NINDS NIH HHS; R01 AG078948 United States AG NIA NIH HHS |
| فهرسة مساهمة: | Keywords: Alzheimer’s Disease; Caspase; FTD; MED; Neurodegeneration; TDP-43; Tau; Tauopathy; co-pathology; mouse model; vulnerable neuron |
| تواريخ الأحداث: | Date Created: 20240709 Latest Revision: 20240816 |
| رمز التحديث: | 20240816 |
| مُعرف محوري في PubMed: | PMC11230425 |
| DOI: | 10.1101/2024.06.26.600814 |
| PMID: | 38979270 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2692-8205 |
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| DOI: | 10.1101/2024.06.26.600814 |