Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency

Evers, B. Mark; Rodríguez-Navas, Carlos; Tesla, Rachel J.; Prange‐Kiel, Janine; Wasser, Catherine R.; Yoo, Kyoung Shin; McDonald, Jeffrey G.; Cenik, Bercin Kutluk; Ravenscroft, Thomas A.; Plattner, Florian; Rademakers, Rosa; Yu, Gang; White, Charles L.; Herz, Joachim

doi:10.1016/j.celrep.2017.08.056

Cited by 106 publications

(102 citation statements)

References 53 publications

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“…Overexpression of human progranulin can rescue toxicity from overexpression of TDP‐43 mutants in zebrafish and heterozygous loss of progranulin enhances toxicity from TDP‐43 overexpression in worms , indicating that haploinsufficiency of progranulin may render neurons susceptible to TDP‐43 toxicity. As in humans, Grn knockout mice display gene‐dosage dependent lysosomal pathology, with upregulation of lysosomal proteins and an increase in the number of lysosomes in both heterozygous and homozygous mice . Perhaps unsurprisingly homozygous knockout mice also present accumulation of lipofuscin, as found in the homozygous disorder NCL .…”

Section: Genetic Models Of Ftdmentioning

confidence: 96%

Review: Modelling the pathology and behaviour of frontotemporal dementia

Solomon

Mitchell

Salcher-Konrad

et al. 2019

Neuropathology Appl Neurobio

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Frontotemporal dementia (FTD) encompasses a collection of clinically and pathologically diverse neurological disorders. Clinical features of behavioural and language dysfunction are associated with neurodegeneration, predominantly of frontal and temporal cortices. Over the past decade, there have been significant advances in the understanding of the genetic aetiology and neuropathology of FTD which have led to the creation of various disease models to investigate the molecular pathways that contribute to disease pathogenesis. The generation of in vivo models of FTD involves either targeting genes with known disease‐causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP‐43 and FUS. This review provides a comprehensive summary of the different in vivo model systems used to understand pathomechanisms in FTD, with a focus on disease models which reproduce aspects of the wide‐ranging behavioural phenotypes seen in people with FTD. We discuss the emerging disease pathways that have emerged from these in vivo models and how this has shaped our understanding of disease mechanisms underpinning FTD. We also discuss the challenges of modelling the complex clinical symptoms shown by people with FTD, the confounding overlap with features of motor neuron disease, and the drive to make models more disease‐relevant. In summary, in vivo models can replicate many pathological and behavioural aspects of clinical FTD, but robust and thorough investigations utilizing shared features and variability between disease models will improve the disease‐relevance of findings and thus better inform therapeutic development.

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Section: Genetic Models Of Ftdmentioning

confidence: 96%

Review: Modelling the pathology and behaviour of frontotemporal dementia

Solomon

Mitchell

Salcher-Konrad

et al. 2019

Neuropathology Appl Neurobio

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“…lipid droplet accumulation, compared to wild type macrophages 78 . In addition, a recent study reported that loss of GRN leads to intracellular and intra-lysosomal accumulation of long polyunsaturated triacylglyerides 79 in the brains of humans and mice. Since triacylglycerides (TAG) are a major component of lipid droplets in LAM, it is possible that lipid droplet accumulation in GRN deficient microglia contributes to elevated TAG levels in brains lacking GRN.…”

Section: Lam In Neurodegenerationmentioning

confidence: 99%

Lipid droplet accumulating microglia represent a dysfunctional and pro-inflammatory state in the aging brain

Marschallinger

Iram

Zardeneta

et al. 2019

Preprint

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Microglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call lipid droplet-accumulating microglia (LAM), are defective in phagocytosis, produce high levels of reactive oxygen species, and secrete proinflammatory cytokines. RNA sequencing analysis of LAM revealed a transcriptional profile driven by innate inflammation distinct from previously reported microglial states. An unbiased CRISPR-Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin, are causes of autosomal dominant forms of human neurodegenerative diseases. We thus propose that LAM contribute to agerelated and genetic forms of neurodegeneration.

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“…Likewise, astrocytes are known to bind and degrade extracellular amyloid-β, a key player in Alzheimer's disease (Wyss-Coray et al, 2003;Koistinaho et al, 2004). Recent work established a strong link of both Parkinson's disease and FTD with lysosomal storage disorders (LSDs) (Deng et al, 2015;Burbulla et al, 2017;Evers et al, 2017). LSDs are a large group of rare inherited metabolic disorders with defective lysosome function resulting in faulty degradation and recycling of cellular constituents.…”

Section: Discussionmentioning

confidence: 99%

Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia

Altmann

Cash

Bocchetta

et al. 2019

Preprint

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Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of FTD (C9orf72, GRN and MAPT), the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work we combined gene expression data for 16,912 genes from the Allen Institute for Brain Science atlas with brain maps of gray matter atrophy in symptomatic C9orf72, GRN and MAPT carriers obtained from the Genetic FTD Initiative study. A set of 405 and 250 genes showed significant positive and negative correlation, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions, i.e., signaling regional resilience to atrophy, is enriched for neuronal genes, while the gene set with increased expression in atrophied regions, i.e., signaling regional vulnerability, is enriched for astrocyte genes. Notably, these results extend earlier findings from proteomic analyses in the same cortical regions of interest comparing healthy controls and patients with FTD. Thus, our analysis indicates that cortical regions showing the most severe atrophy in genetic FTD are those with the highest astrocyte density in healthy subjects. Therefore, astrocytes may play a more active role in the onset of neurodegeneration in FTD than previously assumed, e.g., through emergence of neurotoxic (A1) astrocytes. Abbreviated summary (50 words):Altmann et al. investigated the concordance between spatial cortical gene expression in healthy subjects and atrophy patterns in genetic frontotemporal dementia. They found that gene expression of astrocyte-related genes was higher in regions with atrophy. Thus, suggesting a more active role of astrocytes in the onset of neurodegeneration.

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Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency

Cited by 106 publications

References 53 publications

Review: Modelling the pathology and behaviour of frontotemporal dementia

Review: Modelling the pathology and behaviour of frontotemporal dementia

Lipid droplet accumulating microglia represent a dysfunctional and pro-inflammatory state in the aging brain

Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia

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