Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis

Boland, Sebastian; Swarup, Sharan; Ambaw, Yohannes Abere; Malia, Pedro Carpio; Richards, Ruth C.; Fischer, Alexander W.; Singh, Simran Jeet; Aggarwal, Geetika; Spina, Salvatore; Nana, Alissa L.; Grinberg, Lea T.; Seeley, William W.; Surma, Michał A.; Klose, Christian; Paulo, João A.; Nguyen, Andrew D.; Walther, Tobias C.; Farese, Robert V.

doi:10.1038/s41467-022-33500-9

Cited by 55 publications

(89 citation statements)

References 55 publications

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“…GRN mutations are proposed to disrupt lysosomal homeostasis, and hypomyelination is common to many lysosomal storage diseases, including neuronal ceroid lipofuscinosis (NCL) caused by homozygous GRN mutations [ 11 , 12 ]. Reduced GCase activity has been reported in G rn-/- mice [ 19 , 43 ], IPSC-derived neurons [ 18 ] and brain tissue from FTD- GRN cases [ 44 , 45 ]. We observed no significant difference in GCase activity between FTD cases and controls, in frontal grey or white matter, or parietal white matter (Fig.…”

Section: Resultsmentioning

confidence: 99%

Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations

Marian

Teo

Lee

et al. 2023

acta neuropathol commun

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Heterozygous mutations in the GRN gene and hexanucleotide repeat expansions in C9orf72 are the two most common genetic causes of Frontotemporal Dementia (FTD) with TDP-43 protein inclusions. The triggers for neurodegeneration in FTD with GRN (FTD-GRN) or C9orf72 (FTD-C9orf72) gene abnormalities are unknown, although evidence from mouse and cell culture models suggests that GRN mutations disrupt lysosomal lipid catabolism. To determine how brain lipid metabolism is affected in familial FTD with TDP-43 inclusions, and how this is related to myelin and lysosomal markers, we undertook comprehensive lipidomic analysis, enzyme activity assays, and western blotting on grey and white matter samples from the heavily-affected frontal lobe and less-affected parietal lobe of FTD-GRN cases, FTD-C9orf72 cases, and age-matched neurologically-normal controls. Substantial loss of myelin-enriched sphingolipids (sulfatide, galactosylceramide, sphingomyelin) and myelin proteins was observed in frontal white matter of FTD-GRN cases. A less-pronounced, yet statistically significant, loss of sphingolipids was also observed in FTD-C9orf72. FTD-GRN was distinguished from FTD-C9orf72 and control cases by increased acylcarnitines in frontal grey matter and marked accumulation of cholesterol esters in both frontal and parietal white matter, indicative of myelin break-down. Both FTD-GRN and FTD-C9orf72 cases showed significantly increased lysosomal and phagocytic protein markers, however galactocerebrosidase activity, required for lysosomal catabolism of galactosylceramide and sulfatide, was selectively increased in FTD-GRN. We conclude that both C9orf72 and GRN mutations are associated with disrupted lysosomal homeostasis and white matter lipid loss, but GRN mutations cause a more pronounced disruption to myelin lipid metabolism. Our findings support the hypothesis that hyperactive myelin lipid catabolism is a driver of gliosis and neurodegeneration in FTD-GRN. Since FTD-GRN is associated with white matter hyperintensities by MRI, our data provides important biochemical evidence supporting the use of MRI measures of white matter integrity in the diagnosis and management of FTD.

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Section: Resultsmentioning

confidence: 99%

Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations

Marian

Teo

Lee

et al. 2023

acta neuropathol commun

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“…Proteomics also identified dysregulation of glycerolipid catabolism in the FTD patient ineurons, and our results are consistent with other proteomics studies using mouse models of PGRN-deficiency. Both Huang et al (2020) 47 and Boland et al (2021) 48 found changes in proteins associated with lipid catabolism in Grn-deficient mouse brain samples 47,48 . We found reduced levels of lysosomal acid lipase (LIPA), which is involved in the hydrolysis of cholesterol esters and triglycerides to release cholesterol and fatty acids, in the PGRN-deficient FTD i-neurons.…”

Section: Discussionmentioning

confidence: 96%

Frontotemporal Dementia Patient Neurons With Progranulin Deficiency Display Protein Dyshomeostasis

Elia

Herting

Alijagic³

et al. 2023

Preprint

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Haploinsufficiency of progranulin (PGRN) causes frontotemporal dementia (FTD), a devastating neurodegenerative disease with no effective treatment. PGRN is required for efficient proteostasis, as loss of neuronal PGRN results in dysfunctional lysosomes and impaired clearance and cytoplasmic aggregation of TDP-43, a protein involved in neurodegeneration in FTD. These and other events lead to neurodegeneration and neuroinflammation. However, the detailed mechanisms leading to protein dyshomeostasis in PGRN-deficient cells remain unclear. We report here the development of human cell models of FTD with PGRN-deficiency to explore the molecular mechanisms underlying proteostasis breakdown and TDP-43 aggregation in FTD. Neurons differentiated from FTD patient induced pluripotent stem cells (iPSCs) have reduced PGRN levels, and the neurons recapitulate key disease features, including impaired lysosomal function, defective TDP-43 turnover and accumulation, neurodegeneration, and death. Proteomic analysis revealed altered levels of proteins linked to the autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS) in FTD patient neurons, providing new mechanistic insights into the link between PGRN-deficiency and disease pathobiology.

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“…The lipidomic profiles in brains of Grn R493X/ R493X mice resemble lipidomic changes in FTD-GRN [120]. Levels of monosialyated-GM1 and di-sialylated GD1 species are significantly elevated in brain tissue from patients with FTD-GRN but not in brain tissue from patients with sporadic-non-GRN FTD [120]. Finally, Grn R493X/R493X mice also exhibit cytoplasmic accumulation of TDP43 and a dramatic reduction in synaptophysin [126].…”

Section: R493x Knock-in Micementioning

confidence: 90%

“…Also, like Grn -/mice, Grn R493X/R493X mice have age-dependent accumulation of ganglioside species mono-sialylated GM1 and di-sialylated GD-3 in areas of the cortex, further supporting the idea that progranulin deficiency impairs sphingolipid degradation. The lipidomic profiles in brains of Grn R493X/ R493X mice resemble lipidomic changes in FTD-GRN [120]. Levels of monosialyated-GM1 and di-sialylated GD1 species are significantly elevated in brain tissue from patients with FTD-GRN but not in brain tissue from patients with sporadic-non-GRN FTD [120].…”

Section: R493x Knock-in Micementioning

confidence: 90%

“…These abnormalities are all modeled in Grn -/mice [86,87,115,116]. Grn -/mice also have deficiency of bis(monoacylglycero)phosphate (BMP) species and glucosylsphingosine accumulation indicating abnormalities in sphingolipid metabolism [117][118][119][120]. Lipofuscinosis and lysosomal dyshomeostasis are apparent in Grn -/mice as early as 6 months of age, while deficits in sphingolipid metabolism start even earlier, at around 3 months of age.…”

Section: Homozygous Knockout Micementioning

confidence: 99%

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Preclinical Interventions in Mouse Models of Frontotemporal Dementia Due to Progranulin Mutations

2023

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Heterozygous loss-of-function mutations in progranulin (GRN) cause frontotemporal dementia (FTD), a leading cause of early-onset dementia characterized clinically by behavioral, social, and language deficits. There are currently no FDA-approved therapeutics for FTD-GRN, but this has been an active area of investigation, and several approaches are now in clinical trials. Here, we review preclinical development of therapies for FTD-GRN with a focus on testing in mouse models. Since most FTD-GRN-associated mutations cause progranulin haploinsufficiency, these approaches focus on raising progranulin levels. We begin by considering the disorders associated with altered progranulin levels, and then review the basics of progranulin biology including its lysosomal, neurotrophic, and immunomodulatory functions. We discuss mouse models of progranulin insufficiency and how they have been used in preclinical studies on a variety of therapeutic approaches. These include approaches to raise progranulin expression from the normal allele or facilitate progranulin production by the mutant allele, as well as approaches to directly increase progranulin levels by delivery across the blood–brain barrier or by gene therapy. Several of these approaches have entered clinical trials, providing hope that new therapies for FTD-GRN may be the next frontier in the treatment of neurodegenerative disease.

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Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis

Cited by 55 publications

References 55 publications

Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations

Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations

Frontotemporal Dementia Patient Neurons With Progranulin Deficiency Display Protein Dyshomeostasis

Preclinical Interventions in Mouse Models of Frontotemporal Dementia Due to Progranulin Mutations

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