Progranulin Mutations as Risk Factors for Alzheimer Disease

Perry, David C.; Lehmann, Manja; Yokoyama, Jennifer S.; Karydas, Anna; Lee, Jason JiYong; Coppola, Giovanni; Grinberg, Lea T.; Geschwind, Dan; Seeley, William W.; Miller, Bruce L.; Rosen, Howard J.; Rabinovici, Gil D.

doi:10.1001/2013.jamaneurol.393

Cited by 118 publications

(85 citation statements)

References 37 publications

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“…30 Similarly, at least one neuropathologically proven AD case was found to harbor a loss-offunction variant of GRN. 31 Apparently consistent with the hypothesis of several genes causing different dementing disorders, Guerreiro et al 32 reported a CADASIL-causing variant of the NOTCH3 gene in a family clinically diagnosed with AD. However, no evidence of an AD pathophysiological process was available, segregation analysis could not be interpreted, co-occurrence of two distinct diseases could not be excluded as consanguinity was observed and a recessive cause of AD-like dementia remained possible.…”

Section: Discussionmentioning

confidence: 72%

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Nicolas¹,

Wallon²,

Charbonnier³

et al. 2015

Eur J Hum Genet

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Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of lateonset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.

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Section: Discussionmentioning

confidence: 72%

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Nicolas¹,

Wallon²,

Charbonnier³

et al. 2015

Eur J Hum Genet

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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: 94%

“…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. Additionally, misregulation of progranulin expression has been implicated in parkinsonism, neuronal ceroid lipofuscinosis, and other neuropsychiatric disorders 10, 11…”

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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“…PGRN is of particular interest in the context of neurodegenerative disease because its haploinsufficiency causes frontotemporal dementia in humans (59,60), and putative roles for PGRN in AD have been proposed (61). Interestingly, it was recently reported (based on genetic perturbations) that microglial PGRN limits amyloid plaque deposition in a mouse AD model (31).…”

Section: Discussionmentioning

confidence: 99%

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Gowrishankar

Yuan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

316

326

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Through a comprehensive analysis of organellar markers in mouse models of Alzheimer’s disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer’s disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer’s disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology.

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Progranulin Mutations as Risk Factors for Alzheimer Disease

Cited by 118 publications

References 37 publications

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

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

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

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