Linking tuberous sclerosis complex, excessive mTOR signaling, and age-related neurodegeneration: a new association between TSC1 mutation and frontotemporal dementia

Olney, Nicholas; Alquézar, Carolina; Ramos, Eliana Marisa; Nana, Alissa L.; Fong, Jamie; Karydas, Anna; Taylor, Joanne; Stephens, Melanie; Argouarch, Andrea; Berlo, Victoria A. Van; Dokuru, Deepika; Sherr, Elliott H.; Jicha, Gregory A.; Dillon, William P.; Desikan, Rahul S.; May, Mary De; Seeley, William W.; Coppola, Giovanni; Miller, Bruce L.; Kao, Aimee W.

doi:10.1007/s00401-017-1764-0

Cited by 12 publications

(38 citation statements)

References 19 publications

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“…Furthermore, loss‐of‐function mutations in the progranulin gene are risk factors for developing AD as well as other neurodegenerative disorders 4, 6, 8. Together these findings suggest that progranulin plays a primarily neuroprotective role, reactively modifying or guarding against neurodegenerative processes.…”

Section: Discussionmentioning

confidence: 93%

“…Granulins and progranulin have been implicated as potent immunomodulators and cell‐cycle regulators. In the CNS, progranulin expression increases with age in both neurons and microglia, and plays a role in neurite outgrowth, synapse modification, and the prevention of neuronal apoptosis 1, 2, 3, 4. This neuroprotective function is highlighted by the relationship between progranulin and neurodegenerative disease; heterozygous loss‐of‐function mutations in the gene encoding progranulin ( GRN ) cause frontotemporal dementia (FTD),5, 6 and a common rs5848 allele in the 3′UTR of GRN has been associated with both decreased serum and brain progranulin expression levels and increased risk of developing Alzheimer's disease (AD) 7, 8, 9.…”

Section: Introductionmentioning

confidence: 99%

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Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment

Cooper

Nachun

Dokuru

et al. 2018

Ann Clin Transl Neurol

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ObjectiveChanges in progranulin (GRN) expression have been hypothesized to alter risk for Alzheimer's disease (AD). We investigated the relationship between GRN expression in peripheral blood and clinical diagnosis of AD and mild cognitive impairment (MCI).MethodsPeripheral blood progranulin gene expression was measured, using microarrays from Alzheimer's (n = 186), MCI (n = 118), and control (n = 204) subjects from the University of California San Francisco Memory and Aging Center (UCSF‐MAC) and two independent published series (AddNeuroMed and ADNI). GRN gene expression was correlated with clinical, demographic, and genetic data, including APOE haplotype and the GRN rs5848 single‐nucleotide polymorphism. Finally, we assessed progranulin protein levels, using enzyme‐linked immunosorbent assay, and methylation status using methylation microarrays.ResultsWe observed an increase in blood progranulin gene expression and a decrease in GRN promoter methylation in males (P = 0.007). Progranulin expression was 13% higher in AD and MCI patients compared with controls in the UCSF‐MAC cohort (F 2,505 = 10.41, P = 3.72*10−5). This finding was replicated in the AddNeuroMed (F 2,271 = 17.9, P = 4.83*10−8) but not the ADNI series. The rs5848 SNP (T‐allele) predicted decreased blood progranulin gene expression (P = 0.03). The APOE4 haplotype was positively associated with progranulin expression independent of diagnosis (P = 0.04). Finally, we did not identify differences in plasma progranulin protein levels or gene methylation between diagnostic categories.InterpretationProgranulin mRNA is elevated in peripheral blood of patients with AD and MCI and its expression is associated with numerous genetic and demographic factors. These data suggest a role in the pathogenesis of neurodegenerative dementias besides frontotemporal dementia.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment

Cooper

Nachun

Dokuru

et al. 2018

Ann Clin Transl Neurol

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“…The first gene to be recognized as such was glucocerebrosidase A (GBA), in which mutations can underlie both Gaucher's and Parkinson's disease (6), but many others have since been identified (7)(8)(9)(10). Recently, we described an individual with FTD who carried a novel, monoallelic loss-of-function (LOF) mutation in the TSC1 gene (11). Until this report, TSC1 mutations had only been associated with tuberous sclerosis complex (TSC), a juvenile-onset neurodevelopmental disorder typified by seizures, cognitive delay, spaceoccupying tumors and skin stigmata (12).…”

Section: Introductionmentioning

confidence: 99%

“…To determine if otherwise cognitively normal adults with TSC exhibited any evidence for pre-morbid cognitive decline, we gathered a cohort of adults with mild TSC and found an age-associated cognitive phenotype consistent with FTD (15). In our earlier studies, TSC1 mutations carriers exhibited evidence of tau accumulation in cell-based models, neuropathology (11) or by positivity on tau positron emission tomography (PET) imaging (15). Thus, clinical, genetic, experimental and neuroimaging data all support an association of TSC1 gene mutations with tauopathy.…”

Section: Introductionmentioning

confidence: 99%

TSC1loss-of-function increases risk for tauopathy by inducing tau acetylation and preventing autophagy-mediated tau clearance

Alquézar

et al. 2020

Preprint

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Age-associated neurodegenerative disorders demonstrating tau-laden intracellular inclusions, including Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD) and progressive supranuclear palsy (PSP), are collectively known as tauopathies. The vast majority of human tauopathies accumulate non-mutant tau rather than mutant forms of the protein, yet cell and animal models for non-mutant tauopathies are lacking. We previously linked a monoallelic mutation in the TSC1 gene to tau accumulation and FTLD. Now, we have identified new variants in TSC1 that predisposed to other tauopathies such as AD and PSP. These new TSC1 risk variants significantly decreased the half-life of TSC1/hamartin in vitro. Cellular and murine models of TSC1 haploinsufficiency (TSC1+/-) accumulated tau protein that exhibited aberrant acetylation on six lysine residues. Tau acetylation hindered its lysosomal degradation via chaperone-mediated autophagy leading to neuronal tau accumulation. Enhanced tau acetylation in TSC1+/- models was achieved through both an increase in p300 acetyltransferase activity and a decrease in SIRT1 deacetylase levels. Pharmacological modulation of either enzyme restored tau levels. Together, these studies substantiate TSC1 as a novel tauopathy risk gene and advance TSC1 haploinsufficiency as a new genetic model for tauopathy. In addition, these results promote acetylated tau as a rational target for diagnostic and therapeutic modalities in multiple tauopathies.

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“…The accumulation of iron or decreased Cp activity in the brain has been associated with neurodegeneration [19]. Thus, Tf and Cp play essential roles in the development of neurodegenerative diseases, including TSC [21].…”

Section: Introductionmentioning

confidence: 99%

Improvement in Impaired Social Cognition but Not Seizures by Everolimus in a Child with Tuberous Sclerosis-Associated Autism through Increased Serum Antioxidant Proteins and Oxidant/Antioxidant Status

Yui

Imataka

Sasaki

et al. 2019

Case Reports in Pediatrics

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We investigated the effect of the mammalian target of rapamycin (mTOR) inhibitor everolimus on tuberous sclerosis complex- (TSC-) associated autistic symptoms and focal seizures with impaired awareness in a female child with TSC. We further evaluated the relationship between improved autistic symptoms and seizures and increased the serum levels of the antioxidant proteins, ceruloplasmin (Cp) and transferrin (Tf), and oxidant-antioxidant status indicated by the oxidant marker oxidized low-density lipoprotein (ox-LDL) and the antioxidant marker total antioxidant power (TAP). Everolimus treatment improved impaired social cognition and autistic behaviors; however, seizure and epileptic activity persisted. Serum Cp and Tf levels gradually increased in response to improved autistic symptoms. Serum TAP levels gradually decreased from baseline to the lowest value at 16 weeks and then increased at 24 weeks, showing a trend toward decreased total score of the Aberrant Behavior Checklist. This study revealed that everolimus treatment improved impaired social cognition with increased serum levels of the copper mediator (Cp) and iron mediator (Tf) via homeostatic control of mTOR activity accompanied by overlap of the oxidant-antioxidant system. Everolimus had no effect on TSC-related epileptiform discharges, and thus, the autistic symptoms and epileptic activity may be two independent end results of a common central nervous system disorder including mTOR hyperactivity. This trial is registered with JMAS-IIA00258.

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Linking tuberous sclerosis complex, excessive mTOR signaling, and age-related neurodegeneration: a new association between TSC1 mutation and frontotemporal dementia

Cited by 12 publications

References 19 publications

Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment

Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment

TSC1loss-of-function increases risk for tauopathy by inducing tau acetylation and preventing autophagy-mediated tau clearance

Improvement in Impaired Social Cognition but Not Seizures by Everolimus in a Child with Tuberous Sclerosis-Associated Autism through Increased Serum Antioxidant Proteins and Oxidant/Antioxidant Status

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