Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease

Jian, Jinlong; Tian, Qingyun; Hettinghouse, Aubryanna; Zhao, Suisheng; Liu, Helen; Wei, Jianlu; Grünig, Gabriele; Zhang, Wujuan; Setchell, Kenneth D.R.; Sun, Ying; Overkleeft, Herman S.; Chan, Gloria; Liu, Chuanju

doi:10.1016/j.ebiom.2016.10.010

Cited by 92 publications

(148 citation statements)

References 56 publications

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“…In further studies, the authors determined that progranulin is required to mobilize GCase to the lysosome in stress conditions, and that it binds directly to GCase and recruits HSP70 to form a complex involving LIMP‐2 to allow for final trafficking to the lysosome. A modified progranulin was found to reduce storage and increase lysosomal localization of GCase in patient fibroblasts (Jian et al., ). Progranulin has been proposed as a chaperone of other lysosomal enzymes, supporting the possible role of progranulin as a modifier of GD and lysosomal function in general (Jian, Hettinghouse, & Liu, ).…”

Section: Modifiers Of Gaucher Disease: Results Of Candidate Gene Studiesmentioning

confidence: 99%

“…Candidate modifiers have helped guide research into potential new therapeutic directions. For example, it was suggested that progranulin might serve as a target for treatment, based on preliminary studies in patient fibroblasts and PGRN‐deficient mice (Jian et al., ). Considering its critical role in GCase activation, LIMP‐2 also can be a potential target for therapy in not only GD, but also other neurological conditions.…”

Section: Modifiers As Targets For Therapeutic Strategiesmentioning

confidence: 99%

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Exploring genetic modifiers of Gaucher disease: The next horizon

et al. 2018

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Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from mutations in the gene GBA1 that lead to a deficiency in the enzyme glucocerebrosidase. Accumulation of the enzyme's substrates, glucosylceramide and glucosylsphingosine, results in symptoms ranging from skeletal and visceral involvement to neurological manifestations. Nonetheless, there is significant variability in clinical presentations amongst patients, with limited correlation between genotype and phenotype. Contributing to this clinical variation are genetic modifiers that influence the phenotypic outcome of the disorder. In this review, we explore the role of genetic modifiers in Mendelian disorders and describe methods to facilitate their discovery. In addition, we provide examples of candidate modifiers of Gaucher disease, explore their relevance in the development of potential therapeutics, and discuss the impact of GBA1 and modifying mutations on other more common diseases like Parkinson disease. Identifying these important modulators of Gaucher phenotype may ultimately unravel the complex relationship between genotype and phenotype and lead to improved counseling and treatments.

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Section: Modifiers Of Gaucher Disease: Results Of Candidate Gene Studiesmentioning

confidence: 99%

Section: Modifiers As Targets For Therapeutic Strategiesmentioning

confidence: 99%

Exploring genetic modifiers of Gaucher disease: The next horizon

et al. 2018

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“…NCL and Gaucher diseases, in which PGRN is implicated, are lysosomal storage disorders. PGRN binds several lysosomal proteins such as sortilin, prosaposin, and β-glucocerebrosidase (Hu et al, 2010; Jian et al, 2016a; Zhou et al, 2015). Lysosomal proteins, which accumulate in NCL, have also been found to accumulate in FTLD-TDP patients with GRN mutations (Gotzl et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice

Klein

Takahashi

et al. 2017

Neuron

144

169

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SUMMARY Progranulin (GRN) and TMEM106B are associated with several common neurodegenerative disorders including frontotemporal lobar degeneration (FTLD). A TMEM106B variant modifies GRN-associated FTLD risk. However, their functional relationship in vivo and the mechanisms underlying the risk modification remain unclear. Here, using transcriptomic and proteomic analyses with Grn−/− and Tmem106b−/− mice, we show that while multiple lysosomal enzymes are increased in Grn−/− brain at both transcriptional and protein levels, TMEM106B deficiency causes reduction in several lysosomal enzymes. Remarkably, Tmem106b deletion from Grn−/− mice normalizes lysosomal protein levels and rescues FTLD-related behavioral abnormalities and retinal degeneration, without improving lipofuscin, C1q or microglial accumulation. Mechanistically, TMEM106B binds vacuolar-ATPase accessory protein 1 (AP1). TMEM106B deficiency reduces vacuolar-ATPase AP1 and V0 subunits, impairing lysosomal acidification and normalizing lysosomal protein levels in Grn−/− neurons. Thus, Grn and Tmem106b genes have opposite effects on lysosomal enzyme levels, and their interaction determines the extent of neurodegeneration.

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“…Notably, the endogenous growth factor progranulin (PGRN) was identified as a natural ligand of TNFRs in 2011 . This ubiquitous molecule has multiple functions, including significant roles in cell proliferation, wound healing, and regulation of immune responses . Interestingly, PGRN functions as a physiological antagonist of TNFR1 and a potent agonist of TNFR2 (with approximately 600‐fold higher binding affinity to TNFR2 than TNF).…”

Section: Selective Tnf Blockadementioning

confidence: 99%

Targeting tumor necrosis factor receptors in ankylosing spondylitis

Lata

Hettinghouse

Liu

2018

Annals of the New York Academy of Sciences

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Over the past two decades, considerable advances in our understanding of inflammatory and immune pathways have allowed for the growing use of targeted biologic therapy. Most notably, the introduction of tumor necrosis factor (TNF) inhibitors has dramatically changed the management of autoimmune inflammatory disorders, including ankylosing spondylitis (AS). Despite the efficacy of TNF inhibitors documented in multiple clinical trials, anti-TNF therapy in AS is far from foolproof; it is associated with serious adverse effects and limited response to therapy in some patients. Moreover, specific questions regarding the role of TNF as a mediator of AS remain unanswered. Therefore, additional efforts are needed in order to better understand the role of TNF in the pathogenesis of AS and to develop safer and more effective treatment strategies. The purpose of this review is to better the understanding of the physiologic and pathogenic roles of TNF signaling in the course of AS. Relevant TNF biology and novel approaches to TNF blockade in AS are discussed.

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Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease

Cited by 92 publications

References 56 publications

Exploring genetic modifiers of Gaucher disease: The next horizon

Exploring genetic modifiers of Gaucher disease: The next horizon

Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice

Targeting tumor necrosis factor receptors in ankylosing spondylitis

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