Sortilin-Mediated Endocytosis Determines Levels of the Frontotemporal Dementia Protein, Progranulin

Hu, Fenghua; Padukkavidana, Thihan; Vægter, Christian Bjerggaard; Brady, Owen A.; Zheng, Y.; Mackenzie, Ian R.; Feldman, Howard; Nykjær, Anders; Strittmatter, Stephen M.

doi:10.1016/j.neuron.2010.09.034

Cited by 482 publications

(567 citation statements)

References 53 publications

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“…These observations suggest that PGRN is delivered to lysosomes by a trafficking route that is distinct from the luminal proteases. One possibility is that at least a portion of neuronal PGRN is acquired by the endocytic uptake in axon terminals of PGRN that is secreted by either neuronal or glial cells (29). Such uptake could either occur through a sortilin-dependent mechanism (29,56) or via the binding of PGRN to a novel plasma membrane receptor.…”

Section: Discussionmentioning

confidence: 99%

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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.

327

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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Section: Discussionmentioning

confidence: 99%

“…6A). Interestingly, PGRN, a protein found within the lysosome lumen, the haploinsufficiency of which causes frontotemporal dementia in humans (29,30), also showed colocalization with LAMP1 in both neuronal cell bodies and at amyloid plaques ( Fig. 6 B and C and Fig.…”

Section: Multiple Lysosomal Proteins Are Enriched Within Plaque-assocmentioning

confidence: 98%

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.

327

326

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“…Although its function is only incompletely understood, progranulin may be a physiological antagonist of tumor necrosis a signaling (Tang et al 2011). It has been reported to act on nerve cells by binding to sortilin following release from activated microglial cells (Hu et al 2010). Mutations in GRN include gene deletions, as well as nonsense, frameshift, and splice-site mutations that cause premature termination, creating null alleles with the mutant RNAs being degraded by nonsense-mediated decay (Van Swieten and Heutink 2008).…”

Section: Mutations In Grnmentioning

confidence: 99%

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

Goedert¹,

Ghetti²,

Spillantini³

2011

Cold Spring Harbor Perspectives in Medicine

138

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“…13 We can postulate that gene alterations or differences in the expression level of progranulin receptors such as sortilin 1 may influence progranulin function. 20 An alternative hypothesis for A9D clinical and pathologic heterogeneity would be unidentified genetic modifiers, which could include known ALS-associated genes. Mutations in the most common ALS-associated genes, SOD1 and C9ORF72, were excluded in the current study.…”

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confidence: 99%

Clinicopathologic variability of the GRN A9D mutation, including amyotrophic lateral sclerosis

et al. 2013

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Objective: We examined the clinical and pathologic phenotypes of GRN mutation carriers with the pathogenic A9D (g.26C.A) missense mutation.Methods: Three patients with GRN A9D mutations were evaluated clinically and came to autopsy with subsequent neuropathologic examination. Results:The clinical diagnoses of patients with GRN A9D mutations were amyotrophic lateral sclerosis, atypical extrapyramidal disorder, and behavioral variant frontotemporal dementia. Immunohistochemistry for TAR DNA-binding protein 43 (TDP-43) revealed variability in morphology and distribution of pathology. One patient had notable involvement of motor neurons in the spinal cord as well as type B TDP-43, whereas 2 other patients had type A TDP-43. Conclusions:The clinical presentation of the GRN A9D missense mutation is not restricted to behavioral variant frontotemporal dementia and may include aphasia, extrapyramidal features, and, notably, amyotrophic lateral sclerosis. Mutations in the progranulin (GRN) gene are a common cause of frontotemporal lobar degeneration (FTLD), with mutations identified in up to 10% of patients with FTLD. 1-3 Behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia are the most frequent clinical presentations, but parkinsonism, corticobasal syndrome, and amnestic syndrome suggesting Alzheimer disease have also been reported. 4 In contrast, pathology associated with GRN mutations is relatively homogeneous, and cortical atrophy tends to be most severe in frontal lobes. 5,6 Atrophy of the parietal lobe and neuronal loss in the substantia nigra occur more often than in FTLD without GRN mutations. TAR DNA-binding protein 43 (TDP-43) is the major pathologic protein in inclusions of FTLD, 7 and GRN mutation carriers have a highly consistent pattern of TDP-43 histopathology. 5,6 The combined experience of investigators at a number of centers where FTLD is regularly seen has led to a harmonized classification system for TDP-43 pathology, with GRN mutation carriers usually exhibiting type A pathology. 8 The majority of GRN mutations promote premature termination of the coding sequence, which results in haploinsufficiency due to nonsense-mediated RNA decay. 1,2 An exception is the A9D (g.26C.A) missense mutation, which results in haploinsufficiency due to loss of GRN secretion. 9 Additional missense, silent, and intronic mutations have unknown pathogenicity or have been identified in controls and are not considered pathogenic (www.molgen.ua.ac.be/ FTDMutations). A few missense mutations of unknown pathogenicity have been reported in patients with amyotrophic lateral sclerosis (ALS) and Alzheimer disease, 10,11 suggesting that GRN variants may increase risk for diseases other than FTLD. Herein, we report that the GRN A9D mutation causes clinical and pathologic heterogeneity, which includes features of ALS.

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Sortilin-Mediated Endocytosis Determines Levels of the Frontotemporal Dementia Protein, Progranulin

Cited by 482 publications

References 53 publications

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

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

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

Clinicopathologic variability of the GRN A9D mutation, including amyotrophic lateral sclerosis

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