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Article ; Online: Implications of Selective Autophagy Dysfunction for ALS Pathology.

Vicencio, Emiliano / Beltrán, Sebastián / Labrador, Luis / Manque, Patricio / Nassif, Melissa / Woehlbier, Ute

2020 Volume 9, Issue 2

Abstract: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder that progressively affects motor neurons in the brain and spinal cord. Due to the biological complexity of the disease, its etiology remains unknown. Several cellular mechanisms ... ...

Abstract	Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder that progressively affects motor neurons in the brain and spinal cord. Due to the biological complexity of the disease, its etiology remains unknown. Several cellular mechanisms involved in the neurodegenerative process in ALS have been found, including the loss of RNA and protein homeostasis, as well as mitochondrial dysfunction. Insoluble protein aggregates, damaged mitochondria, and stress granules, which contain RNA and protein components, are recognized and degraded by the autophagy machinery in a process known as selective autophagy. Autophagy is a highly dynamic process whose dysregulation has now been associated with neurodegenerative diseases, including ALS, by numerous studies. In ALS, the autophagy process has been found deregulated in both familial and sporadic cases of the disease. Likewise, mutations in genes coding for proteins involved in the autophagy machinery have been reported in ALS patients, including selective autophagy receptors. In this review, we focus on the role of selective autophagy in ALS pathology.
MeSH term(s)	Amyotrophic Lateral Sclerosis/pathology ; Amyotrophic Lateral Sclerosis/physiopathology ; Amyotrophic Lateral Sclerosis/therapy ; Animals ; Autophagy ; Humans ; Models, Biological ; Signal Transduction
Language	English
Publishing date	2020-02-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9020381
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Article: The Enigmatic Role of C9ORF72 in Autophagy.

Nassif, Melissa / Woehlbier, Ute / Manque, Patricio A

Frontiers in neuroscience

2017 Volume 11, Page(s) 442

Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the loss of motor neurons resulting in a progressive and irreversible muscular paralysis. Advances in large-scale genetics and genomics have revealed intronic ...

Abstract	Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the loss of motor neurons resulting in a progressive and irreversible muscular paralysis. Advances in large-scale genetics and genomics have revealed intronic hexanucleotide repeat expansions in the gene encoding C9ORF72 as a main genetic cause of ALS and frontotemporal dementia (FTD), the second most common cause of early-onset dementia after Alzheimer's disease. Novel insights regarding the underlying pathogenic mechanisms of C9ORF72 seem to suggest a synergy of loss and gain of toxic function during disease. C9ORF72, thus far, has been found to be involved in homeostatic cellular pathways, such as actin dynamics, regulation of membrane trafficking, and macroautophagy. All these pathways have been found compromised in the pathogenesis of ALS. In this review, we aim to summarize recent findings on the function of C9ORF72, particularly in the macroautophagy pathway, hinting at a requirement to maintain the fine balance of macroautophagy to prevent neurodegeneration.
Language	English
Publishing date	2017-08-03
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2017.00442
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Article ; Online: The autophagy protein Def8 is altered in Alzheimer's disease and Aβ42-expressing Drosophila brains.

Oyarce-Pezoa, Sebastián / Rucatti, Guilherme Gischkow / Muñoz-Carvajal, Francisco / Sanhueza, Nicole / Gomez, Wileidy / Espinoza, Sandra / Leiva, Mario / García, Nicolás / Ponce, Daniela P / SanMartín, Carol D / Rojas-Rivera, Diego / Salvadores, Natalia / Behrens, Maria I / Woehlbier, Ute / Calegaro-Nassif, Melissa / Sanhueza, Mario

Scientific reports

2023 Volume 13, Issue 1, Page(s) 17137

Abstract: Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by protein accumulation in the brain as a main neuropathological hallmark. Among them, Aβ42 peptides tend to aggregate and create oligomers and plaques. Macroautophagy, ...

Abstract	Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by protein accumulation in the brain as a main neuropathological hallmark. Among them, Aβ42 peptides tend to aggregate and create oligomers and plaques. Macroautophagy, a form of autophagy characterized by a double-membrane vesicle, plays a crucial role in maintaining neuronal homeostasis by degrading protein aggregates and dysfunctional organelles as a quality control process. Recently, DEF8, a relatively uncharacterized protein, has been proposed as a participant in vesicular traffic and autophagy pathways. We have reported increased DEF8 levels in lymphocytes from mild cognitive impairment (MCI) and early-stage AD patients and a neuronal profile in a murine transgenic AD model. Here, we analyzed DEF8 localization and levels in the postmortem frontal cortex of AD patients, finding increased levels compared to healthy controls. To evaluate the potential function of DEF8 in the nervous system, we performed an in silico assessment of its expression and network profiles, followed by an in vivo evaluation of a neuronal Def8 deficient model using a Drosophila melanogaster model of AD based on Aβ42 expression. Our findings show that DEF8 is an essential protein for maintaining cellular homeostasis in the nervous system, and it is upregulated under stress conditions generated by Aβ42 aggregation. This study suggests DEF8 as a novel actor in the physiopathology of AD, and its exploration may lead to new treatment avenues.
MeSH term(s)	Animals ; Humans ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Autophagy/genetics ; Brain/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Peptide Fragments/metabolism
Chemical Substances	Amyloid beta-Peptides ; amyloid beta-protein (1-42) ; Peptide Fragments
Language	English
Publishing date	2023-10-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-44203-6
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Article ; Online: The Autophagy Protein Pacer Positively Regulates the Therapeutic Potential of Mesenchymal Stem Cells in a Mouse Model of DSS-Induced Colitis.

Bergmann, Cristian A / Beltran, Sebastian / Vega-Letter, Ana Maria / Murgas, Paola / Hernandez, Maria Fernanda / Gomez, Laura / Labrador, Luis / Cortés, Bastián I / Poblete, Cristian / Quijada, Cristobal / Carrion, Flavio / Woehlbier, Ute / Manque, Patricio A

Cells

2022 Volume 11, Issue 9

Abstract: Mesenchymal stem cells (MSC) have emerged as a promising tool to treat inflammatory diseases, such as inflammatory bowel disease (IBD), due to their immunoregulatory properties. Frequently, IBD is modeled in mice by using dextran sulfate sodium (DSS)- ... ...

Abstract	Mesenchymal stem cells (MSC) have emerged as a promising tool to treat inflammatory diseases, such as inflammatory bowel disease (IBD), due to their immunoregulatory properties. Frequently, IBD is modeled in mice by using dextran sulfate sodium (DSS)-induced colitis. Recently, the modulation of autophagy in MSC has been suggested as a novel strategy to improve MSC-based immunotherapy. Hence, we investigated a possible role of Pacer, a novel autophagy enhancer, in regulating the immunosuppressive function of MSC in the context of DSS-induced colitis. We found that Pacer is upregulated upon stimulation with the pro-inflammatory cytokine TNFα, the main cytokine released in the inflammatory environment of IBD. By modulating Pacer expression in MSC, we found that Pacer plays an important role in regulating the autophagy pathway in this cell type in response to TNFα stimulation, as well as in regulating the immunosuppressive ability of MSC toward T-cell proliferation. Furthermore, increased expression of Pacer in MSC enhanced their ability to ameliorate the symptoms of DSS-induced colitis in mice. Our results support previous findings that autophagy regulates the therapeutic potential of MSC and suggest that the augmentation of autophagic capacity in MSC by increasing Pacer levels may have therapeutic implications for IBD.
MeSH term(s)	Animals ; Autophagy ; Colitis/drug therapy ; Colitis/therapy ; Cytokines/metabolism ; Dextran Sulfate/pharmacology ; Disease Models, Animal ; Inflammatory Bowel Diseases/metabolism ; Mesenchymal Stem Cell Transplantation/methods ; Mesenchymal Stem Cells/metabolism ; Mice ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Cytokines ; Tumor Necrosis Factor-alpha ; Dextran Sulfate (9042-14-2)
Language	English
Publishing date	2022-04-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11091503
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Article: Modulating stress responses by the UPRosome: a matter of life and death.

Woehlbier, Ute / Hetz, Claudio

Trends in biochemical sciences

2011 Volume 36, Issue 6, Page(s) 329–337

Abstract: The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR) through the activation of specialized sensors including inositol-requiring enzyme-1α (IRE1α). IRE1α signals by assembling a dynamic ... ...

Abstract	The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR) through the activation of specialized sensors including inositol-requiring enzyme-1α (IRE1α). IRE1α signals by assembling a dynamic protein platform referred to as the UPRosome, where different modulator and adaptor proteins assemble to regulate the kinetics and amplitude of UPR effector responses. Conversely, chronic ER stress can cause apoptosis. Recent evidence indicates that several apoptosis-related proteins interact with IRE1α, regulating its prosurvival activities and performing a dual function in the regulation of cell death and adaptation to stress. Based on the increasing relevance of ER stress to the occurrence of diverse pathological conditions, strategies to target and modulate the assembly and composition of the UPRosome could have therapeutic benefits for disease intervention.
MeSH term(s)	Animals ; Apoptosis ; Endoplasmic Reticulum/metabolism ; Endoribonucleases/metabolism ; Humans ; Protein-Serine-Threonine Kinases/metabolism ; Signal Transduction ; Stress, Physiological ; Unfolded Protein Response
Chemical Substances	ERN1 protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Endoribonucleases (EC 3.1.-)
Language	English
Publishing date	2011-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	194216-5
ISSN	1362-4326 ; 0968-0004 ; 0376-5067
ISSN (online)	1362-4326
ISSN	0968-0004 ; 0376-5067
DOI	10.1016/j.tibs.2011.03.001
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Zs.A 1207: Show issues

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Article ; Online: Linked homozygous BMPR1B and PDHA2 variants in a consanguineous family with complex digit malformation and male infertility.

Yıldırım, Yeşerin / Ouriachi, Toufik / Woehlbier, Ute / Ouahioune, Wahiba / Balkan, Mahmut / Malik, Sajid / Tolun, Aslıhan

European journal of human genetics : EJHG

2018 Volume 26, Issue 6, Page(s) 876–885

Abstract: In affected members of a consanguineous family, a syndrome, which is concurrence of set of medical signs, is often observed and commonly assumed to have arisen from pleiotropy, i.e., the phenomenon of a single gene variant affecting multiple traits. We ... ...

Abstract	In affected members of a consanguineous family, a syndrome, which is concurrence of set of medical signs, is often observed and commonly assumed to have arisen from pleiotropy, i.e., the phenomenon of a single gene variant affecting multiple traits. We detected six sibs afflicted with a unique combination of digit malformation that includes brachydactyly, symphalangism and zygodactyly plus infertility in males owing to azoospermia, sperm immotility or necrospermia, which we hypothesised to have arisen from a defect in a single gene. We mapped the disease locus and by exome sequencing identified in patients homozygous missense variants bone morphogenetic protein receptor type IB (BMPR1B) c.640C>T (p.(Arg214Cys)) and alpha-2 pyruvate dehydrogenase (PDHA2) c.679A>G (p.(Met227Val)). Structural protein modelling, protein sequence conservation and in silico analysis indicate that both variants affect protein function. BMPR1B is known to be responsible for autosomal dominant brachydactyly and autosomal recessive acromesomelic chondrodysplasia. Our findings show that also recessive complex digit malformation can be caused by BMPR1B variant and not all biallelic BMPR1B variants cause acromesomelic dysplasia. PDHA2 is a novel candidate gene for male infertility; the protein product is a mitochondrial enzyme with highest expression in ejaculated sperm. Our findings are a unique example of two linked variants, ~ 711 Kb apart, in different genes that together manifest as a novel syndrome. They demonstrate that exome sequencing and not candidate gene approach should be employed in disease gene hunt, defining new diseases and genetic testing, to rule out the coincidental presence of two variants contributing together to the phenotype, which may be discerned as a novel disease.
MeSH term(s)	Adult ; Amino Acid Sequence ; Bone Morphogenetic Protein Receptors, Type I/genetics ; Brachydactyly/genetics ; Brachydactyly/physiopathology ; Dwarfism/genetics ; Dwarfism/physiopathology ; Exome ; Female ; Foot Deformities, Congenital/genetics ; Foot Deformities, Congenital/physiopathology ; Genetic Testing ; Hand Deformities, Congenital/genetics ; Hand Deformities, Congenital/physiopathology ; Homozygote ; Humans ; Infertility, Male/epidemiology ; Infertility, Male/genetics ; Infertility, Male/physiopathology ; Male ; Osteochondrodysplasias/genetics ; Osteochondrodysplasias/physiopathology ; Pedigree ; Phenotype ; Pyruvate Dehydrogenase (Lipoamide)/genetics ; Syndactyly/genetics ; Syndactyly/physiopathology ; Synostosis/genetics ; Synostosis/physiopathology
Chemical Substances	PDHA2 protein, human (EC 1.2.4.1) ; Pyruvate Dehydrogenase (Lipoamide) (EC 1.2.4.1) ; BMPR1B protein, human (EC 2.7.11.30) ; Bone Morphogenetic Protein Receptors, Type I (EC 2.7.11.30)
Language	English
Publishing date	2018-03-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/s41431-018-0121-7
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Zs.A 3589: Show issues

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Jg. 1995 - 2021: Lesesall (2.OG)
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Article ; Online: Homozygous mutation in

Yıldız Bölükbaşı, Esra / Mumtaz, Sara / Afzal, Muhammad / Woehlbier, Ute / Malik, Sajid / Tolun, Aslıhan

Journal of medical genetics

2017 Volume 55, Issue 3, Page(s) 189–197

Abstract: Background: Bardet-Biedl syndrome (BBS) is a ciliopathy with extensive phenotypic variability and genetic heterogeneity. We aimed to discover the gene mutated in a consanguineous kindred with multiple cases of a BBS phenotype.: Methods: SNP genotype ... ...

Abstract	Background: Bardet-Biedl syndrome (BBS) is a ciliopathy with extensive phenotypic variability and genetic heterogeneity. We aimed to discover the gene mutated in a consanguineous kindred with multiple cases of a BBS phenotype. Methods: SNP genotype data were used for linkage analysis and exome sequencing to identify mutations. Modelling and in silico analysis were performed to predict mutation severity. Results: Patients had postaxial polydactyly plus variable other clinical features including rod-cone dystrophy, obesity, intellectual disability, renal malformation, developmental delay, dental anomalies, speech disorder and enlarged fatty liver. The 4.57 Mb disease locus harboured homozygous, truncating Conclusion: CEP19
MeSH term(s)	Adolescent ; Adult ; Bardet-Biedl Syndrome/complications ; Bardet-Biedl Syndrome/genetics ; Bardet-Biedl Syndrome/pathology ; Cell Cycle Proteins/genetics ; Female ; Fingers/abnormalities ; Fingers/pathology ; Genetic Linkage ; Homozygote ; Humans ; Male ; Middle Aged ; Mutation ; Obesity, Morbid/genetics ; Obesity, Morbid/pathology ; Polydactyly/complications ; Polydactyly/genetics ; Polydactyly/pathology ; Polymorphism, Single Nucleotide/genetics ; Toes/abnormalities ; Toes/pathology ; Whole Exome Sequencing/methods ; Young Adult ; Zinc Finger Protein GLI1/genetics
Chemical Substances	CEP19 protein, human ; Cell Cycle Proteins ; GLI1 protein, human ; Zinc Finger Protein GLI1
Language	English
Publishing date	2017-11-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	220881-7
ISSN	1468-6244 ; 0022-2593
ISSN (online)	1468-6244
ISSN	0022-2593
DOI	10.1136/jmedgenet-2017-104758
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Zs.A 177: Show issues

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Article ; Online: Endoplasmic reticulum stress leads to accumulation of wild-type SOD1 aggregates associated with sporadic amyotrophic lateral sclerosis.

Medinas, Danilo B / Rozas, Pablo / Martínez Traub, Francisca / Woehlbier, Ute / Brown, Robert H / Bosco, Daryl A / Hetz, Claudio

Proceedings of the National Academy of Sciences of the United States of America

2018 Volume 115, Issue 32, Page(s) 8209–8214

Abstract: Abnormal modifications to mutant superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (fALS). Misfolding of wild-type SOD1 ( ... ...

Abstract	Abnormal modifications to mutant superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (fALS). Misfolding of wild-type SOD1 (SOD1
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Aging/pathology ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/pathology ; Animals ; Astrocytes/pathology ; Brain/cytology ; Brain/drug effects ; Brain/pathology ; Cell Line ; Disease Models, Animal ; Endoplasmic Reticulum Stress/drug effects ; Endoplasmic Reticulum Stress/physiology ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Middle Aged ; Motor Neurons ; Mutation ; Oxidation-Reduction ; Protein Aggregation, Pathological/genetics ; Protein Aggregation, Pathological/pathology ; Protein Folding ; Proteostasis/physiology ; Spinal Cord/cytology ; Spinal Cord/drug effects ; Spinal Cord/pathology ; Superoxide Dismutase-1/genetics ; Superoxide Dismutase-1/metabolism ; Tryptophan/metabolism ; Tunicamycin/pharmacology ; Unfolded Protein Response/physiology
Chemical Substances	SOD1 protein, human ; Tunicamycin (11089-65-9) ; Tryptophan (8DUH1N11BX) ; Superoxide Dismutase-1 (EC 1.15.1.1)
Language	English
Publishing date	2018-07-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1801109115
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Zs.A 1148: Show issues

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Article ; Online: DEF8 and Autophagy-Associated Genes Are Altered in Mild Cognitive Impairment, Probable Alzheimer's Disease Patients, and a Transgenic Model of the Disease.

Leyton, Esteban / Matus, Diego / Espinoza, Sandra / Benitez, José Matías / Cortés, Bastián I / Gomez, Wileidy / Arévalo, Nohela B / Murgas, Paola / Manque, Patricio / Woehlbier, Ute / Duran-Aniotz, Claudia / Hetz, Claudio / Behrens, María Isabel / SanMartín, Carol D / Nassif, Melissa

Journal of Alzheimer's disease : JAD

2021 Volume 82, Issue s1, Page(s) S163–S178

Abstract: Background: Disturbances in the autophagy/endolysosomal systems are proposed as early signatures of Alzheimer's disease (AD). However, few studies are available concerning autophagy gene expression in AD patients.: Objective: To explore the ... ...

Abstract	Background: Disturbances in the autophagy/endolysosomal systems are proposed as early signatures of Alzheimer's disease (AD). However, few studies are available concerning autophagy gene expression in AD patients. Objective: To explore the differential expression of classical genes involved in the autophagy pathway, among them a less characterized one, DEF8 (Differentially expressed in FDCP 8), initially considered a Rubicon family member, in peripheralblood mononuclear cells (PBMCs) from individuals with mild cognitive impairment (MCI) and probable AD (pAD) and correlate the results with the expression of DEF8 in the brain of 5xFAD mice. Method: By real-time PCR and flow cytometry, we evaluated autophagy genes levels in PBMCs from MCI and pAD patients. We evaluated DEF8 levels and its localization in brain samples of the 5xFAD mice by real-time PCR, western blot, and immunofluorescence. Results: Transcriptional levels of DEF8 were significantly reduced in PBMCs of MCI and pAD patients compared with healthy donors, correlating with the MoCA and MoCA-MIS cognitive tests scores. DEF8 protein levels were increased in lymphocytes from MCI but not pAD, compared to controls. In the case of brain samples from 5xFAD mice, we observed a reduced mRNA expression and augmented protein levels in 5xFAD compared to age-matched wild-type mice. DEF8 presented a neuronal localization. Conclusion: DEF8, a protein proposed to act at the final step of the autophagy/endolysosomal pathway, is differentially expressed in PBMCs of MCI and pAD and neurons of 5xFAD mice. These results suggest a potential role for DEF8 in the pathophysiology of AD.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Animals ; Autophagy/physiology ; Biomarkers/metabolism ; Brain/metabolism ; Brain/pathology ; Cognitive Dysfunction/genetics ; Cognitive Dysfunction/metabolism ; Cognitive Dysfunction/pathology ; Female ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/physiology ; Male ; Mice ; Mice, Transgenic ; Middle Aged
Chemical Substances	Biomarkers ; DEF8 protein, human ; Intracellular Signaling Peptides and Proteins
Language	English
Publishing date	2021-02-22
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-201264
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Zs.A 6084: Show issues

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Article ; Online: Neuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer's Disease.

Cells

2022 Volume 11, Issue 12

Abstract: Alzheimer's disease (AD) is the most prevalent age-associated neurodegenerative disease. A decrease in autophagy during aging contributes to brain disorders by accumulating potentially toxic substrates in neurons. Rubicon is a well-established inhibitor ... ...

Abstract	Alzheimer's disease (AD) is the most prevalent age-associated neurodegenerative disease. A decrease in autophagy during aging contributes to brain disorders by accumulating potentially toxic substrates in neurons. Rubicon is a well-established inhibitor of autophagy in all cells. However, Rubicon participates in different pathways depending on cell type, and little information is currently available on neuronal Rubicon's role in the AD context. Here, we investigated the cell-specific expression of Rubicon in postmortem brain samples from AD patients and 5xFAD mice and its impact on amyloid β burden in vivo and neuroblastoma cells. Further, we assessed Rubicon levels in human-induced pluripotent stem cells (hiPSCs), derived from early-to-moderate AD and in postmortem samples from severe AD patients. We found increased Rubicon levels in AD-hiPSCs and postmortem samples and a notable Rubicon localization in neurons. In AD transgenic mice lacking Rubicon, we observed intensified amyloid β burden in the hippocampus and decreased Pacer and p62 levels. In APP-expressing neuroblastoma cells, increased APP/amyloid β secretion in the medium was found when Rubicon was absent, which was not observed in cells depleted of Atg5, essential for autophagy, or Rab27a, required for exosome secretion. Our results propose an uncharacterized role of Rubicon on APP/amyloid β homeostasis, in which neuronal Rubicon is a repressor of APP/amyloid β secretion, defining a new way to target AD and other similar diseases therapeutically.
MeSH term(s)	Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Autophagy-Related Proteins/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Mice ; Mice, Transgenic ; Neuroblastoma/metabolism ; Neurodegenerative Diseases/metabolism ; Neurons/metabolism
Chemical Substances	Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Autophagy-Related Proteins ; Intracellular Signaling Peptides and Proteins ; RUBCN protein, human
Language	English
Publishing date	2022-06-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11121860
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