cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.19360994
title: Follicular lymphoma-associated mutations in the V-ATPase chaperone VMA21 activate autophagy creating a targetable dependency

description: The discovery of recurrent mutations in subunits and regulators of the vacuolar-type H<sup>+</sup>-translocating ATPase (V-ATPase) in follicular lymphoma (FL) highlights a role for macroautophagy/autophagy, amino-acid, and nutrient-sensing pathways in the pathogenesis of this disease. Here, we report on novel mutations in the ER-resident chaperone VMA21, which is involved in V-ATPase assembly in 12% of FL. Mutations in a novel VMA21 hotspot (p.93X) result in the removal of a C-terminal non-canonical ER retrieval signal thus causing VMA21 mislocalization to lysosomes. The resulting impairment in V-ATPase activity prevents full lysosomal acidification and function, including impaired pH-dependent protein degradation as shown via lysosomal metabolomics and ultimately causes a degree of amino acid depletion in the cytoplasm. These deficiencies result in compensatory autophagy activation, as measured using multiple complementary assays in human and yeast cells. Of translational significance, the compensatory activation of autophagy creates a dependency for survival for VMA21-mutated primary human FL as shown using inhibitors to ULK1, the proximal autophagy-regulating kinase. Using high-throughput microscopy-based screening assays for autophagy-inhibiting compounds, we identify multiple clinical grade cyclin-dependent kinase inhibitors as promising drugs and thus provide new rationale for innovative clinical trials in FL harboring aberrant V-ATPase. <b>Abbreviations:</b> ALs: autolysosomes; APs: autophagosomes; ER: endoplasmic reticulum; FL: follicular lymphoma; GFP: green fluorescent protein; IP: immunoprecipitation; LE/LY: late endosomes/lysosomes; Lyso-IP: lysosomal immunoprecipitation; OST: oligosaccharide transferase; prApe1: precursor aminopeptidase I; SEP: super ecliptic pHluorin; V-ATPase: vacuolar-type H<sup>+</sup>-translocating ATPase
DOI: 10.6084/m9.figshare.19360994.v1
title: Follicular lymphoma-associated mutations in the V-ATPase chaperone VMA21 activate autophagy creating a targetable dependency

description: The discovery of recurrent mutations in subunits and regulators of the vacuolar-type H<sup>+</sup>-translocating ATPase (V-ATPase) in follicular lymphoma (FL) highlights a role for macroautophagy/autophagy, amino-acid, and nutrient-sensing pathways in the pathogenesis of this disease. Here, we report on novel mutations in the ER-resident chaperone VMA21, which is involved in V-ATPase assembly in 12% of FL. Mutations in a novel VMA21 hotspot (p.93X) result in the removal of a C-terminal non-canonical ER retrieval signal thus causing VMA21 mislocalization to lysosomes. The resulting impairment in V-ATPase activity prevents full lysosomal acidification and function, including impaired pH-dependent protein degradation as shown via lysosomal metabolomics and ultimately causes a degree of amino acid depletion in the cytoplasm. These deficiencies result in compensatory autophagy activation, as measured using multiple complementary assays in human and yeast cells. Of translational significance, the compensatory activation of autophagy creates a dependency for survival for VMA21-mutated primary human FL as shown using inhibitors to ULK1, the proximal autophagy-regulating kinase. Using high-throughput microscopy-based screening assays for autophagy-inhibiting compounds, we identify multiple clinical grade cyclin-dependent kinase inhibitors as promising drugs and thus provide new rationale for innovative clinical trials in FL harboring aberrant V-ATPase. <b>Abbreviations:</b> ALs: autolysosomes; APs: autophagosomes; ER: endoplasmic reticulum; FL: follicular lymphoma; GFP: green fluorescent protein; IP: immunoprecipitation; LE/LY: late endosomes/lysosomes; Lyso-IP: lysosomal immunoprecipitation; OST: oligosaccharide transferase; prApe1: precursor aminopeptidase I; SEP: super ecliptic pHluorin; V-ATPase: vacuolar-type H<sup>+</sup>-translocating ATPase
DOI: 10.6084/m9.figshare.19360996
title: Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models

description: Parkinson disease (PD) is a neurodegenerative disorder characterized by the abnormal intracellular accumulation of SNCA/α-synuclein. While the exact mechanisms underlying SNCA pathology are not fully understood, increasing evidence suggests the involvement of autophagy as well as lysosomal deficiencies. Because CTSD (cathepsin D) has been proposed to be the major lysosomal protease involved in SNCA degradation, its deficiency has been linked to the presence of insoluble SNCA conformers in the brain of mice and humans as well as to the transcellular transmission of SNCA aggregates. We here postulate that SNCA degradation can be enhanced by the application of the recombinant human proform of CTSD (rHsCTSD). Our results reveal that rHsCTSD is efficiently endocytosed by neuronal cells, correctly targeted to lysosomes and matured to an enzymatically active protease. In dopaminergic neurons derived from induced pluripotent stem cells (iPSC) of PD patients harboring the A53T mutation within the <i>SNCA</i> gene, we confirm the reduction of insoluble SNCA after treatment with rHsCTSD. Moreover, we demonstrate a decrease of pathological SNCA conformers in the brain and within primary neurons of a <i>ctsd</i>-deficient mouse model after dosing with rHsCTSD. Boosting lysosomal CTSD activity not only enhanced SNCA clearance in human and murine neurons as well as tissue, but also restored endo-lysosome and autophagy function. Our findings indicate that CTSD is critical for SNCA clearance and function. Thus, enzyme replacement strategies utilizing CTSD may also be of therapeutic interest for the treatment of PD and other synucleinopathies aiming to decrease the SNCA burden. <b>Abbreviations:</b> aa: amino acid; SNCA/α-synuclein: synuclein alpha; APP: amyloid beta precursor protein; BBB: blood brain barrier; BF: basal forebrain; CBB: Coomassie Brilliant Blue; CLN: neuronal ceroid lipofuscinosis; CNL10: neuronal ceroid lipofuscinosis type 10; Corr.: corrected; CTSD: cathepsin D; CTSB: cathepsin B; DA: dopaminergic; DA-iPSn: induced pluripotent stem cell-derived dopaminergic neurons; dox: doxycycline; ERT: enzyme replacement therapy; Fx: fornix, GBA/β-glucocerebrosidase: glucosylceramidase beta; h: hour; HC: hippocampus; HT: hypothalamus; i.c.: intracranially; IF: immunofluorescence; iPSC: induced pluripotent stem cell; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LSDs: lysosomal storage disorders; MAPT: microtubule associated protein tau; M6P: mannose-6-phosphate; M6PR: mannose-6-phosphate receptor; MB: midbrain; mCTSD: mature form of CTSD; neurofil.: neurofilament; PD: Parkinson disease; proCTSD: proform of CTSD; PRNP: prion protein; RFU: relative fluorescence units; rHsCTSD: recombinant human proCTSD; SAPC: Saposin C; SIM: structured illumination microscopy; T-insol: Triton-insoluble; T-sol: Triton-soluble; TEM: transmission electron microscopy, TH: tyrosine hydroxylase; Thal: thalamus
DOI: 10.6084/m9.figshare.19360996.v2
title: Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models

description: Parkinson disease (PD) is a neurodegenerative disorder characterized by the abnormal intracellular accumulation of SNCA/α-synuclein. While the exact mechanisms underlying SNCA pathology are not fully understood, increasing evidence suggests the involvement of autophagy as well as lysosomal deficiencies. Because CTSD (cathepsin D) has been proposed to be the major lysosomal protease involved in SNCA degradation, its deficiency has been linked to the presence of insoluble SNCA conformers in the brain of mice and humans as well as to the transcellular transmission of SNCA aggregates. We here postulate that SNCA degradation can be enhanced by the application of the recombinant human proform of CTSD (rHsCTSD). Our results reveal that rHsCTSD is efficiently endocytosed by neuronal cells, correctly targeted to lysosomes and matured to an enzymatically active protease. In dopaminergic neurons derived from induced pluripotent stem cells (iPSC) of PD patients harboring the A53T mutation within the <i>SNCA</i> gene, we confirm the reduction of insoluble SNCA after treatment with rHsCTSD. Moreover, we demonstrate a decrease of pathological SNCA conformers in the brain and within primary neurons of a <i>ctsd</i>-deficient mouse model after dosing with rHsCTSD. Boosting lysosomal CTSD activity not only enhanced SNCA clearance in human and murine neurons as well as tissue, but also restored endo-lysosome and autophagy function. Our findings indicate that CTSD is critical for SNCA clearance and function. Thus, enzyme replacement strategies utilizing CTSD may also be of therapeutic interest for the treatment of PD and other synucleinopathies aiming to decrease the SNCA burden. <b>Abbreviations:</b> aa: amino acid; SNCA/α-synuclein: synuclein alpha; APP: amyloid beta precursor protein; BBB: blood brain barrier; BF: basal forebrain; CBB: Coomassie Brilliant Blue; CLN: neuronal ceroid lipofuscinosis; CNL10: neuronal ceroid lipofuscinosis type 10; Corr.: corrected; CTSD: cathepsin D; CTSB: cathepsin B; DA: dopaminergic; DA-iPSn: induced pluripotent stem cell-derived dopaminergic neurons; dox: doxycycline; ERT: enzyme replacement therapy; Fx: fornix, GBA/β-glucocerebrosidase: glucosylceramidase beta; h: hour; HC: hippocampus; HT: hypothalamus; i.c.: intracranially; IF: immunofluorescence; iPSC: induced pluripotent stem cell; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LSDs: lysosomal storage disorders; MAPT: microtubule associated protein tau; M6P: mannose-6-phosphate; M6PR: mannose-6-phosphate receptor; MB: midbrain; mCTSD: mature form of CTSD; neurofil.: neurofilament; PD: Parkinson disease; proCTSD: proform of CTSD; PRNP: prion protein; RFU: relative fluorescence units; rHsCTSD: recombinant human proCTSD; SAPC: Saposin C; SIM: structured illumination microscopy; T-insol: Triton-insoluble; T-sol: Triton-soluble; TEM: transmission electron microscopy, TH: tyrosine hydroxylase; Thal: thalamus
DOI: 10.6084/m9.figshare.19360996.v1
title: Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models

description: Parkinson disease (PD) is a neurodegenerative disorder characterized by the abnormal intracellular accumulation of SNCA/α-synuclein. While the exact mechanisms underlying SNCA pathology are not fully understood, increasing evidence suggests the involvement of autophagic as well as lysosomal deficiencies. Because CTSD (cathepsin D) has been proposed to be the major lysosomal protease involved in SNCA degradation, its deficiency has been linked to the presence of insoluble SNCA conformers in the brain of mice and humans as well as to the transcellular transmission of SNCA aggregates. We here postulate that SNCA degradation can be enhanced by the application of the recombinant human proform of CTSD (rHsCTSD). Our results reveal that rHsCTSD is efficiently endocytosed by neuronal cells, correctly targeted to lysosomes and matured to an enzymatically active protease. In dopaminergic neurons derived from induced pluripotent stem cells (iPSC) of PD patients harboring the A53T mutation within the <i>SNCA</i> gene, we confirm the reduction of insoluble SNCA after treatment with rHsCTSD. Moreover, we demonstrate a decrease of pathological SNCA conformers in the brain and within primary neurons of a CTSD-deficient mouse model after dosing with rHsCTSD. Boosting lysosomal CTSD activity not only enhanced SNCA clearance, but also restored endo-lysosome and autophagy function in human and murine neurons as well as tissue. Our findings indicate that CTSD is critical for SNCA clearance and function. Thus, enzyme replacement strategies utilizing CTSD may also be of therapeutic interest for the treatment of PD and other synucleinopathies aiming to decrease the SNCA burden.
DOI: 10.6084/m9.figshare.19360996.v3
title: Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models

description: Parkinson disease (PD) is a neurodegenerative disorder characterized by the abnormal intracellular accumulation of SNCA/α-synuclein. While the exact mechanisms underlying SNCA pathology are not fully understood, increasing evidence suggests the involvement of autophagy as well as lysosomal deficiencies. Because CTSD (cathepsin D) has been proposed to be the major lysosomal protease involved in SNCA degradation, its deficiency has been linked to the presence of insoluble SNCA conformers in the brain of mice and humans as well as to the transcellular transmission of SNCA aggregates. We here postulate that SNCA degradation can be enhanced by the application of the recombinant human proform of CTSD (rHsCTSD). Our results reveal that rHsCTSD is efficiently endocytosed by neuronal cells, correctly targeted to lysosomes and matured to an enzymatically active protease. In dopaminergic neurons derived from induced pluripotent stem cells (iPSC) of PD patients harboring the A53T mutation within the <i>SNCA</i> gene, we confirm the reduction of insoluble SNCA after treatment with rHsCTSD. Moreover, we demonstrate a decrease of pathological SNCA conformers in the brain and within primary neurons of a <i>ctsd</i>-deficient mouse model after dosing with rHsCTSD. Boosting lysosomal CTSD activity not only enhanced SNCA clearance in human and murine neurons as well as tissue, but also restored endo-lysosome and autophagy function. Our findings indicate that CTSD is critical for SNCA clearance and function. Thus, enzyme replacement strategies utilizing CTSD may also be of therapeutic interest for the treatment of PD and other synucleinopathies aiming to decrease the SNCA burden. <b>Abbreviations:</b> aa: amino acid; SNCA/α-synuclein: synuclein alpha; APP: amyloid beta precursor protein; BBB: blood brain barrier; BF: basal forebrain; CBB: Coomassie Brilliant Blue; CLN: neuronal ceroid lipofuscinosis; CNL10: neuronal ceroid lipofuscinosis type 10; Corr.: corrected; CTSD: cathepsin D; CTSB: cathepsin B; DA: dopaminergic; DA-iPSn: induced pluripotent stem cell-derived dopaminergic neurons; dox: doxycycline; ERT: enzyme replacement therapy; Fx: fornix, GBA/β-glucocerebrosidase: glucosylceramidase beta; h: hour; HC: hippocampus; HT: hypothalamus; i.c.: intracranially; IF: immunofluorescence; iPSC: induced pluripotent stem cell; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LSDs: lysosomal storage disorders; MAPT: microtubule associated protein tau; M6P: mannose-6-phosphate; M6PR: mannose-6-phosphate receptor; MB: midbrain; mCTSD: mature form of CTSD; neurofil.: neurofilament; PD: Parkinson disease; proCTSD: proform of CTSD; PRNP: prion protein; RFU: relative fluorescence units; rHsCTSD: recombinant human proCTSD; SAPC: Saposin C; SIM: structured illumination microscopy; T-insol: Triton-insoluble; T-sol: Triton-soluble; TEM: transmission electron microscopy, TH: tyrosine hydroxylase; Thal: thalamus
DOI: 10.48597/smmk-7nf6
title: Carbon_dioxide at MNL-CAN

description: Measurement of Carbon_dioxide at MNL-CAN
DOI: 10.48597/svup-uy3p
title: Carbon_dioxide at MNL-CAN

description: Measurement of Carbon_dioxide at MNL-CAN
DOI: 10.48597/t8ej-m4mp
title: Dinitrogen_monoxide at CCS-FRA

description: Measurement of Dinitrogen_monoxide at CCS-FRA
DOI: 10.48597/u2vp-n6zk
title: Sulfur_hexafluoride at CCS-FRA

description: Measurement of Sulfur_hexafluoride at CCS-FRA
DOI: 10.48597/uawv-3uhx
title: Carbon_dioxide at FRA-DEN

description: Measurement of Carbon_dioxide at FRA-DEN
DOI: 10.48597/ufvh-kx9v
title: Longitude at MNL-CAN

description: Measurement of Longitude at MNL-CAN
DOI: 10.48597/umgq-z3qt
title: Sulfur_hexafluoride at FRA-CCS

description: Measurement of Sulfur_hexafluoride at FRA-CCS
DOI: 10.48597/ux8k-cnuc
title: Dinitrogen_monoxide at MNL-CAN

description: Measurement of Dinitrogen_monoxide at MNL-CAN
DOI: 10.48597/v2cz-k5jf
title: Sulfur_hexafluoride at FRA-DEN

description: Measurement of Sulfur_hexafluoride at FRA-DEN
DOI: 10.48597/v8b6-ue57
title: Longitude at MNL-CAN

description: Measurement of Longitude at MNL-CAN
DOI: 10.48597/vgdd-m4ap
title: Dinitrogen_monoxide at MAA-FRA

description: Measurement of Dinitrogen_monoxide at MAA-FRA
DOI: 10.48597/vqr4-cjax
title: Altitude at FRA-CCS

description: Measurement of Altitude at FRA-CCS
DOI: 10.48597/w3ku-8gew
title: Methane at FRA-CPT

description: Measurement of Methane at FRA-CPT
DOI: 10.48597/weh8-mmr6
title: Methane at MNL-CAN

description: Measurement of Methane at MNL-CAN
DOI: 10.48597/xppk-3bpq
title: Carbon_dioxide at FRA-CPT

description: Measurement of Carbon_dioxide at FRA-CPT
DOI: 10.48597/xtkt-rgty
title: Dinitrogen_monoxide at FRA-DEN

description: Measurement of Dinitrogen_monoxide at FRA-DEN
DOI: 10.48597/yby6-8w64
title: Carbon_dioxide at FRA-CCS

description: Measurement of Carbon_dioxide at FRA-CCS
DOI: 10.48597/ysn4-jahs
title: Altitude at CCS-FRA

description: Measurement of Altitude at CCS-FRA
DOI: 10.48597/yye3-zmnk
title: Altitude at MNL-CAN

description: Measurement of Altitude at MNL-CAN
DOI: 10.48597/z8j3-maex
title: Dinitrogen_monoxide at CCS-FRA

description: Measurement of Dinitrogen_monoxide at CCS-FRA
DOI: 10.48597/zg3j-y49a
title: Sulfur_hexafluoride at MNL-CAN

description: Measurement of Sulfur_hexafluoride at MNL-CAN
DOI: 10.48597/zyu7-fh3z
title: Methane at FRA-CCS

description: Measurement of Methane at FRA-CCS
DOI: 10.48597/zyyv-awvy
title: Methane at FRA-CCS

description: Measurement of Methane at FRA-CCS
DOI: 10.48597/29qh-nrcw
title: Measurement of Susp_part_matter at Zarra

description: Measurement of Susp_part_matter at Zarra
DOI: 10.48597/3fz7-bjh4
title: Measurement of Inorganics in air and particle phase at Niembro

description: Measurement of Inorganics in air and particle phase at Niembro
DOI: 10.48597/3k98-4haa
title: Measurement of Susp_part_matter at Niembro

description: Measurement of Susp_part_matter at Niembro
DOI: 10.48597/4y2d-ycng
title: Measurement of Susp_part_matter at Niembro

description: Measurement of Susp_part_matter at Niembro
DOI: 10.48597/5web-h2hy
title: Measurement of Inorganics in air and particle phase at Niembro

description: Measurement of Inorganics in air and particle phase at Niembro
DOI: 10.48597/5x78-rckt
title: Measurement of Sulphate_total at Niembro

description: Measurement of Sulphate_total at Niembro
DOI: 10.48597/778v-2fe2
title: Measurement of Susp_part_matter at Zarra

description: Measurement of Susp_part_matter at Zarra
DOI: 10.48597/7v9c-a7yk
title: Measurement of Inorganics in air and particle phase at Niembro

description: Measurement of Inorganics in air and particle phase at Niembro
DOI: 10.48597/7vpx-mwu3
title: Measurement of Inorganics in air and particle phase at Campisabalos

description: Measurement of Inorganics in air and particle phase at Campisabalos
DOI: 10.48597/bsbv-g4rq
title: Measurement of Sulphate_total at Campisabalos

description: Measurement of Sulphate_total at Campisabalos
DOI: 10.48597/e9x6-jkk4
title: Measurement of Susp_part_matter at Niembro

description: Measurement of Susp_part_matter at Niembro
DOI: 10.48597/esfr-zx94
title: Measurement of Sulphate_total at Niembro

description: Measurement of Sulphate_total at Niembro
DOI: 10.48597/et8x-4kjv
title: Measurement of Inorganics in air and particle phase at Niembro

description: Measurement of Inorganics in air and particle phase at Niembro
DOI: 10.48597/fcfa-gtnz
title: Measurement of Sum_ammonia_and_ammonium at Campisabalos

description: Measurement of Sum_ammonia_and_ammonium at Campisabalos
DOI: 10.48597/fsrr-45gb
title: Measurement of Inorganics in air and particle phase at Niembro

description: Measurement of Inorganics in air and particle phase at Niembro
DOI: 10.48597/fzjs-ac8h
title: Measurement of Susp_part_matter at Niembro

description: Measurement of Susp_part_matter at Niembro
DOI: 10.48597/j452-8pec
title: Measurement of Inorganics in air and particle phase at Campisabalos

description: Measurement of Inorganics in air and particle phase at Campisabalos
DOI: 10.48597/javy-sqc3
title: Measurement of Inorganics in air and particle phase at Niembro

description: Measurement of Inorganics in air and particle phase at Niembro
DOI: 10.48597/jd2f-x9dt
title: Measurement of Sulphate_total at Barcarrota

description: Measurement of Sulphate_total at Barcarrota
DOI: 10.48597/qn3p-jktf
title: Measurement of Sulphate_total at Barcarrota

description: Measurement of Sulphate_total at Barcarrota
DOI: 10.48597/qvgr-3xex
title: Measurement of Sulphate_total at Barcarrota

description: Measurement of Sulphate_total at Barcarrota
DOI: 10.48597/qz2g-g3wd
title: Measurement of Sulphate_total at Niembro

description: Measurement of Sulphate_total at Niembro
DOI: 10.6084/m9.figshare.9923951
title: Genetic polymorphisms of 20 autosomal STR loci in the Han population of Putian City, Southeastern China

description: <i>Background</i>: Short tandem repeats (STRs) are genetic markers that are more informative than single nucleotide polymorphisms and they are widely used in forensic DNA analysis. <i>Aim</i>: To carry out the genetic analysis of 20 autosomal STR loci in Han individuals of Putian City, Southeast China, to expand the available population information for human genetic databases and forensic analysis. <i>Subjects and methods</i>: Saliva swabs from 1417 unrelated Chinese Han individuals from Putian City of Southeast China were collected and then genotyped using the SureID<sup>®</sup> 21G Human STR Identification Kit. Moreover, phylogenetic analysis based on the Nei’s standard genetic distance was performed between the Han population and other relevant populations based on the shared autosomal STR genotyping. <i>Results</i>: We found 272 alleles among 1417 unrelated individuals and the corresponding allelic frequencies ranged from 0.5409 to 0.0004. The combined power of exclusion (CPE) was 0.999999995514, and the combined power of discrimination (CPD) was 0.9999999999999999999999994061. Population comparison revealed that the Putian Han population makes a cluster with other Han populations from China while showing significant differences when compared with other worldwide populations. <i>Conclusions</i>: Our results found that the SureID<sup>®</sup> 21G Human STR Identification Kit panel was appropriate for forensic identity testing and paternity testing. Putian Han population had a closer genetic relationship with Han populations from other regions in China, while other minorities like Uighurs and Kazakhs from China showed significant differences.