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Progranulin–glucocerebrosidase complex regulates tau and alpha-synuclein inclusions to alter phenotypes in tauopathy

ABSTRACT: Many neurodegenerative disorders including Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are characterized by abnormal protein deposition and frequently show comorbid pathology. Progranulin (PGRN) is implicated not only in TDP-43 but in tau and alpha-synuclein proteinopathies. However, the underlying mechanisms are unknown. Here, we generated P301S tau transgenic mice with PGRN haploinsufficiency and loss and found that those mice exhibit exacerbated disinhibition phenotype while showing attenuated memory impairment, hippocampal atrophy, and transcriptomic changes. Remarkably, the phenotypic alteration was accompanied by an increase in tau inclusions, which are positive for alpha-synuclein, a PGRN binding partner beta-glucocerebrosidase (GCase), and its substrate glucosylceramide. GCase inhibition or PGRN deficiency enhanced tau aggregation induced by AD-derived tau seeds in neurons. In vitro, GCase and glucosylceramide promoted P301S tau aggregation. Similar co-pathology was observed in AD and FTLD-GRN patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE180672 | GEO | 2024/01/18

REPOSITORIES: GEO

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TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4

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2022-11-30 | GSE206368 | GEO

Are Mouse Models a surrogate for human disease? A temporal, quantitative and molecular perspective.

Project description:It is unclear to what extent Tau molecular pathology in murine models reflect human Tauopathies. Nevertheless, mouse models that overexpress human mutant Tau (P301S and P301L) are widely used in studies of Tauopathies and Alzheimer’s Disease (AD). In this study, we perform an in-depth temporally and spatially resolved mass spectrometry-based proteomic analysis of P301S (hTau.P301S) and P301L (rTg(tauP301L)4510) mice as well as human patients with AD or frontotemporal dementia due to the P301L mutation, to identify differences and similarities between human AD, animal models and human P301L patients. Both mouse models and human P301L patients show progressive Tau accumulation driven by Tau phosphorylation during disease progression as also observed in early human AD. However, Tau ubiquitination and acetylation, important in human AD, are less or not represented in the mouse models or in P301L patients. Our analyses provide guidance regarding designing mechanistic studies and testing of Tau directed therapeutics.

2023-02-03 | PXD033965 | Pride

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Project description:Many RNA-binding proteins (RBPs), particularly those associated with RNA granules, promote pathological protein aggregation in neurodegenerative diseases. Here, we demonstrate that G3BP2, a core component of stress granules, directly interacts with Tau and inhibits Tau aggregation. In the human brain, the interaction of G3BP2 and Tau is dramatically increased in multiple Tauopathies and precedes neurofibrillary tangle (NFT) formation in Alzheimer’s disease (AD). Surprisingly, Tau pathology is significantly elevated upon loss of G3BP2 in human neurons and brain organoids. Moreover, we find that G3BP2 masks the microtubule-binding region (MTBR) of Tau, thereby inhibiting Tau aggregation. Our study defines a novel role for RBPs as a line of defense against Tau aggregation in Tauopathies.

2023-05-17 | GSE226624 | GEO

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2021-03-24 | GSE169478 | GEO

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Project description:Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer’s disease (AD) with APOE4 increasing and APOE2 decreasing risk relative to APOE3. In the P301S mouse model of tauopathy, ApoE4 increases tau pathology and neurodegeneration when compared to ApoE3 or the absence of ApoE. However, the role of ApoE isoforms in regulating lipid metabolism in the setting of tauopathy is unknown. Here, by using targeted lipidomics coupled with histological analysis, we demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation along with significant perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via administration of the LXR agonist GW3965 reduces lipid droplet accumulation in primary E4 microglia in vitro and GW3965 or Abca1 overexpression strongly attenuates tau pathology, neurodegeneration, and synapse loss in P301S/ApoE4 mice. By immunostaining, bulk and snRNA sequencing, we demonstrate reductions in reactive astrocytes and microglia as well as significant changes in cholesterol biosynthesis and metabolism in glia of tauopathy mice in response to LXR activation. These data suggest that promoting efflux of glial lipids via Abca1 could serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration.

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Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist

2023-12-08 | GSE242180 | GEO

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2019-06-23 | GSE118473 | GEO

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Project description:Progranulin (PGRN) haploinsufficiency is a major risk factor for Frontotemporal Lobar Degeneration with TDP-43 pathology (FTLD-TDP). Protein replacement therapeutic strategies are currently in clinical development, intended to restore PGRN levels in the central nervous system and slow or halt disease progression. However, such approaches require repeated dosing. Here, we explored the use of adeno-associated virus (AAV) to achieve sustained expression of a brain penetrant PGRN fusion protein, composed of a single chain variable fragment (scFv) recognizing mouse transferrin receptor (TfR) fused to human PGRN (AAV(L):bPGRN). We evaluated this approach for its ability to rescue pathological phenotypes in a double knockout mouse model lacking both PGRN and TMEM106b. A single administration of AAV(L):bPGRN reduced FTLD-TDP associated pathologies including severe motor function deficits, formation of insoluble, abnormally processed and phosphorylated TDP-43, as well as dysfunctional protein degradation, lipid dysregulation and gliosis.

2023-07-16 | GSE235515 | GEO

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Project description:The most common genetic risk factors for Parkinson’s disease (PD) are a set of heterozygous mutant (MT) alleles of the GBA1 gene that encodes -glucocerebrosidase (GCase), an enzyme that is normally trafficked from the endoplasmic reticulum and Golgi apparatus to the lysosomal lumen. We examined isolated lysosomes from anterior cingulate cortex, a region of high alpha-synuclein accumulation in GBA-PD, and found that while lysosomal GCase is entirely luminal in healthy controls, half of the lysosomal GBA-PD GCase was present on the lysosomal surface. This lysosomal mislocalization is dependent on a pentapeptide motif in GCase used for targeting of cytosolic proteins to lysosomes for degradation by chaperone-mediated autophagy (CMA), a type of autophagy inhibited by PD-related pathogenic proteins including -synuclein and LRRK2. Single cell transcriptional analysis and comparative proteomics of brains from GBA-PD patients demonstrated reduced CMA activity and overall proteome changes similar to those observed in mouse models with CMA blockage. We found that the delivery of unfolded mutant GCase to lysosomes decreased CMA due to recognition of unfolded mutant GCase to the chaperone hsc70, and the resulting complex binds the CMA receptor LAMP2A at the lysosomal surface. Unfolded mutant GCase is a poor substrate for translocation into the lysosomal lumen, and by interfering with LAMP2A multimerization, blocks the translocation and causes cytosolic accumulation of other CMA substrates including -synuclein and tau. In primary substantia nigra dopamine neurons, MT GCase led to neuronal death, while loss of the GCase CMA motif or deletion of -synuclein rescued the neurons. These results indicate how MT GCase alleles may converge with other PD proteins to block CMA function and produce -synuclein accumulation.

2022-02-03 | PXD028656 | Pride

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