Progranulin as a therapeutic target in neurodegenerative diseases

Rhinn, Hervé; Tatton, Nadine; McCaughey, Stella Mayo; Kurnellas, Michael; Rosenthal, Arnon

doi:10.1016/j.tips.2021.11.015

Cited by 90 publications

(92 citation statements)

References 93 publications

(108 reference statements)

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“…Progranulin Gene (GRN) plays a key role in the development, survival and function of mammalian neuronal cells and microglia, and it regulates lysosomal biogenesis, inflammation, repair, stress response and aging responses. 31 GRN mutations are associated with one third of inherited frontotemporal dementias. 32 Circulating GRN is a potential biomarker for screening patients with Alzheimer-type dementia and mild cognitive impairment.…”

Section: Discussionmentioning

confidence: 99%

Proteomics Combined with RNA Sequencing to Screen Biomarkers of Sepsis

Wang¹,

Li²,

Li³

et al. 2022

IDR

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Purpose To screen biomarkers in the serum of patients with sepsis by proteomics combined with RNA sequencing technology, and to find new diagnostic and therapeutic targets for sepsis. Patients and Methods Blood samples of 22 sepsis patients (sepsis group) and 10 healthy volunteers (normal group) were collected from January 2019 to December 2020. Data-independent acquisition (DIA) method was employed for protein profiling, RNA sequencing was employed for gene sequencing. Subsequently, quality control and differential analysis (FC≥2; FDR<0.05) of DIA data and RNA sequencing data were performed. Then we identified expression trend-consistent divergence factors by nine-quadrant analysis; subsequent protein-protein interaction (PPI) and gene ontology (GO) functional enrichment analysis of intersection factors was performed, and meta-analysis of targets at transcriptome level was implemented using public datasets. Finally, five Peripheral blood mononuclear cell (PBMC) samples (NC=2; SIRS=1; SEPSIS =2) were collected, and cell localization analysis of core genes was performed by 10× single-cell RNA sequencing (scRNA-seq). Results Compared with the normal group, there were 4681 differentially expressed genes and 202 differentially expressed proteins in the sepsis group. Among them, 25 factors were expressed in both proteome and transcriptome, and the analysis of PPI and GO found that they were mainly involved in biological processes such as white blood cell and neutrophil response, inflammatory and immune response. Four core genes GSTO1, C1QA, RETN, and GRN were screened by meta-analysis, all of which were highly expressed in the sepsis group compared with the normal group (P<0.05); scRNA-seq showed the core genes were mainly localized in macrophage cell lines. Conclusion The core genes GSTO1, C1QA, RETN and GRN are mainly expressed in macrophages, widely involved in inflammation and immune responses, and are highly expressed in plasma in the sepsis, suggesting that they may become potential research targets for sepsis.

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Section: Discussionmentioning

confidence: 99%

Proteomics Combined with RNA Sequencing to Screen Biomarkers of Sepsis

Wang¹,

Li²,

Li³

et al. 2022

IDR

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“…In addition to rare loss of function GRN mutations, single-nucleotide polymorphisms (SNPs) in the GRN locus, such as rs5848, rs2269906 and rs850738, have been identified by genome-wide association studies as genetic determinants of other neurologic diseases, including Alzheimer’s disease, limbic-predominant age-related TDP-43 encephalopathy (LATE), amyotrophic lateral-sclerosis (ALS) and FTLD caused by expansion of C9orf72 and Gaucher disease [ 23 ]. All these SNPs have been related to decreased levels of circulating progranulin, which have also been reported in idiopathic Parkinson disease and autism [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…All these SNPs have been related to decreased levels of circulating progranulin, which have also been reported in idiopathic Parkinson disease and autism [ 24 , 25 ]. This commonality in a risk gene for neurodegeneration is almost unheard of and suggests that progranulin is a critical regulator of brain health, constituting a uniquely attractive therapeutic target [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Generation and Characterization of Novel iPSC Lines from a Portuguese Family Bearing Heterozygous and Homozygous GRN Mutations

et al. 2022

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Mutations in granulin (GRN) have been associated with neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). In Portugal, GRN mutations account for around half of all FTLD cases with known genetic origin. Here, we describe the generation and characterization of three human-induced pluripotent stem cell (hiPSC) lines from a Portuguese family harboring heterozygous and homozygous GRN mutation. hiPSCs were reprogrammed from human dermal fibroblasts by episomal nucleofection of the Yamanaka factors. The new generated lines were positive for pluripotency markers, could be further differentiated to cells expressing all trilineage markers, and presented a normal karyotype. They were also capable of differentiating into 3D brain organoids and presented a significant decrease in progranulin protein levels. Hence, these cell lines constitute suitable new tools to elucidate the pathophysiological mechanisms associated with the GRN mutations in the context of FTLD.

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“…Mutations in GRN, the gene that encodes PGRN, cause familial frontotemporal lobar dementia (FTLD) and Lewy body dementia (LBD) [ 14 , 15 ]. Several drug development efforts in FTLD target PGRN [ 16 ]. PGRN and PSAP form a dimer and facilitate each other’s trafficking both intracellularly and extracellularly [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Decreased Prosaposin and Progranulin in the Cingulate Cortex Are Associated with Schizophrenia Pathophysiology

Zhang

Flais

et al. 2022

IJMS

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Prosaposin (PSAP) and progranulin (PGRN) are two lysosomal proteins that interact and modulate the metabolism of lipids, particularly sphingolipids. Alterations in sphingolipid metabolism have been found in schizophrenia. Genetic associations of PSAP and PGRN with schizophrenia have been reported. To further clarify the role of PSAP and PGRN in schizophrenia, we examined PSAP and PGRN levels in postmortem cingulate cortex tissue from healthy controls along with patients who had suffered from schizophrenia, bipolar disorder, or major depressive disorder. We found that PSAP and PGRN levels are reduced specifically in schizophrenia patients. To understand the role of PSAP in the cingulate cortex, we used an AAV strategy to knock down PSAP in neurons located in this region. Neuronal PSAP knockdown led to the downregulation of neuronal PGRN levels and behavioral abnormalities. Cingulate-PSAP-deficient mice exhibited increased anxiety-like behavior and impaired prepulse inhibition, as well as intact locomotion, working memory, and a depression-like state. The behavioral changes were accompanied by increased early growth response protein 1 (EGR-1) and activity-dependent cytoskeleton-associated protein (ARC) levels in the sensorimotor cortex and hippocampus, regions implicated in circuitry dysfunction in schizophrenia. In conclusion, PSAP and PGRN downregulation in the cingulate cortex is associated with schizophrenia pathophysiology.

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Progranulin as a therapeutic target in neurodegenerative diseases

Cited by 90 publications

References 93 publications

Proteomics Combined with RNA Sequencing to Screen Biomarkers of Sepsis

Proteomics Combined with RNA Sequencing to Screen Biomarkers of Sepsis

Generation and Characterization of Novel iPSC Lines from a Portuguese Family Bearing Heterozygous and Homozygous GRN Mutations

Decreased Prosaposin and Progranulin in the Cingulate Cortex Are Associated with Schizophrenia Pathophysiology

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