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2.
PLoS Biol ; 17(12): e3000525, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31841517

RESUMO

Ubiquitin-specific protease (USP) 6 is a hominoid deubiquitinating enzyme previously implicated in intellectual disability and autism spectrum disorder. Although these findings link USP6 to higher brain function, potential roles for USP6 in cognition have not been investigated. Here, we report that USP6 is highly expressed in induced human neurons and that neuron-specific expression of USP6 enhances learning and memory in a transgenic mouse model. Similarly, USP6 expression regulates N-methyl-D-aspartate-type glutamate receptor (NMDAR)-dependent long-term potentiation and long-term depression in USP6 transgenic mouse hippocampi. Proteomic characterization of transgenic USP6 mouse cortex reveals attenuated NMDAR ubiquitination, with concomitant elevation in NMDAR expression, stability, and cell surface distribution with USP6 overexpression. USP6 positively modulates GluN1 expression in transfected cells, and USP6 down-regulation impedes focal GluN1 distribution at postsynaptic densities and impairs synaptic function in neurons derived from human embryonic stem cells. Together, these results indicate that USP6 enhances NMDAR stability to promote synaptic function and cognition.

3.
Front Immunol ; 10: 2470, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681336

RESUMO

Allogeneic hematopoietic stem cell transplant (allo-HSCT) is often used to treat acute leukemia or defects of hematopoiesis. Its widespread use is hampered by graft-vs.-host disease (GVHD), which has high morbidity and mortality in both acute and chronic subtypes. Chronic GVHD (cGVHD) occurs most frequently in skin and often is characterized by pathogenic fibrosis. Mast cells (MCs) are known to be involved in the pathogenesis of other fibrotic diseases. In a murine model of cGVHD after allo-HSCT, C57BL/6J recipients of allogeneic LP/J donor cells develop sclerodermatous dermal cGVHD which is significantly decreased in mast cell-deficient B6.Cg-KitW-sh/HNihrJaeBsmGlliJ recipients. The presence of MCs is associated with fibrosis, chemokine production, and recruitment of GVHD effector cells to the skin. Chemokine production by MCs is blocked by drugs used to treat cGVHD. The importance of MCs in skin cGVHD is mirrored by increased MCs in the skin of patients with dermal cGVHD. We show for the first time a role for MCs in skin cGVHD that may be targetable for preventive and therapeutic intervention in this disease.

4.
Am J Speech Lang Pathol ; : 1-17, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31682766

RESUMO

Purpose Many children with developmental disorders experience difficulty mastering grammatical forms, including children with developmental language disorder and a subset of children with autism spectrum disorder (ASD). One of the key language features in both of these populations is a weakness in the expressive use of grammatical forms. There is a paucity of studies that evaluate the effectiveness of interventions targeting grammatical forms for populations other than developmental language disorder. The current study evaluated a combined explicit-implicit intervention approach to teach grammatical forms to children with ASD symptomology. Method Researchers used a single-subject, nonconcurrent multiple baseline, A-B-C study design. Three children with characteristics of ASD (2 with formal diagnoses) between the ages of 5 and 9 years participated in treatment targeting a weak grammatical structure. After baseline, each participant completed a series of treatment sessions that comprised implicit instruction, followed by a series of treatment sessions that incorporated explicit instruction. Accuracy of use was assessed during each session across baseline, implicit-only, and explicit-implicit conditions as well as 1 week, 1 month, and 2 months posttreatment. Results All participants produced target forms with low accuracy across baseline and implicit-only treatment sessions. Within three explicit-implicit treatment sessions, all participants demonstrated a marked increase in level and upward trend in their production accuracy. Gains in accuracy were maintained 2 months posttreatment for 2 of the 3 participants. Conclusions The current study provides preliminary evidence to support the use of explicit approaches to teach grammatical forms to children with ASD symptomology and motivates further investigation in this area.

5.
Transplantation ; 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31634333

RESUMO

BACKGROUND: Gastrointestinal acute graft-versus-host disease (aGVHD) occurring after allogeneic hematopoietic cell transplant (allo-HCT) is an alloreactive T cell- and inflammatory cytokine driven organ injury with epithelial apoptosis as one of its hallmark findings, and is associated with significant mortality. Tumor necrosis factor (TNF)-alpha-induced protein 8 (TNFAIP8 or TIPE) acts as a negative mediator of apoptosis via inhibition of caspase-3 activation, promotes cell proliferation and Tipe deficiency is associated with increased inflammation. METHODS: To evaluate the role of TIPE in acute GVHD, naive C57BL/6 and Tipe C57BL/6 mice were conditioned with 1000cGy single dose total-body irradiation, followed by transplantation of 10 million bone marrow (BM) cells and 20 million splenocytes from either syngeneic C57BL/6 or allogeneic BALB/c donors. RESULTS: Allo TIPE-deficient mice developed exacerbated gut GVHD compared to allo controls and had significantly decreased survival (6 weeks OS: 85% vs 37%; p<0.05), higher clinical GVHD scores, more profound weight loss, increased serum proinflammatory cytokines (IL-17A, TNF, IL-6, IFN-y). T cell infiltration into the ileum was increased; epithelial proliferation was decreased along with significantly higher levels of chemokines KC and MIG. Using BM chimeric experiments, TIPE was found to have a role in both hematopoietic and nonhematopoietic cells. CONCLUSIONS: Absence of TIPE results in excessive inflammation and tissue injury after allo HCT, supporting that TIPE confers immune homeostasis and has tissue-protective function during the development of gut GVHD, and may be a potential future target to prevent or treat this complication after allogeneic HCT.

6.
Front Cell Neurosci ; 13: 410, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31551717

RESUMO

Dysregulation of various APP trafficking components in the endosome has been previously implicated in Alzheimer's disease (AD). Although single nucleotide polymorphisms within the gene locus encoding the endosomal component, SNX8 have been previously associated with AD, how SNX8 levels are altered and its contribution to AD onset is currently unknown. Here, we observe decreased expression of SNX8 in human AD and AD mouse brain. SNX8 predominantly localized to early and late endosomes, where SNX8 overexpression enhanced total APP levels, cell surface APP distribution and consequent soluble APPα cleavage. SNX8 depletion resulted in elevated ß-amyloid (Aß) levels, while SNX8 overexpression reduced Aß levels in cells and in an APP/PS1 AD mouse model. Importantly, SNX8 overexpression rescued cognitive impairment in APP/PS1 mice. Together, these results implicate a neuroprotective role for SNX8 in enhancing non-amyloidogenic APP trafficking and processing pathways. Given that endosomal dysfunction is an early event in AD, restoration of dysfunctional endosomal components such as SNX8 may be beneficial in future therapeutic strategies.

7.
Front Aging Neurosci ; 11: 243, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31551758

RESUMO

Oxidative stress is a common feature of neurodegenerative diseases and plays an important role in disease progression. Appoptosin is a pro-apoptotic protein that contributes to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. However, whether appoptosin mediates oxidative stress-induced neurotoxicity has yet to be determined. Here, we observe that appoptosin protein levels are induced by hydrogen peroxide (H2O2) exposure through the inhibition of proteasomal appoptosin degradation. Furthermore, we demonstrate that overexpression of appoptosin induces apoptosis through the JNK-FoxO1 pathway. Importantly, knockdown of appoptosin can ameliorate H2O2-induced JNK activation and apoptosis in primary neurons. Thus, we propose that appoptosin functions as an upstream regulator of the JNK-FoxO1 pathway, contributing to cell death in response to oxidative stress during neurodegeneration.

8.
Neuron ; 103(5): 747-749, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487521

RESUMO

TREM2 and CD33 are microglial receptors associated with Alzheimer's disease (AD) risk. In this issue of Neuron, Griciuc et al. (2019) demonstrate opposing effects of CD33 and TREM2 on AD phenotypes, where CD33 deletion promotes neuroprotection in a manner dependent on TREM2.

9.
Mol Cancer Ther ; 18(11): 1973-1984, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31358661

RESUMO

Krüppel-like factor 5 (KLF5), a member of the SP/KLF family of zinc finger transcription factors, is overexpressed in human colorectal cancer specimens, and this overabundance is associated with aggressive cancer development and progression. We demonstrated that mice haploinsufficient for Klf5 had reduced intestinal tumor burden in the background of germline mutation in Apc, a gatekeeper of intestinal tumorigenesis. Based on a high-throughput screening strategy, we developed ML264, a small-molecule compound that inhibits KLF5, and showed that it inhibits growth of colorectal cancer in vitro and in vivo Through optimization efforts based on the structure of ML264, we have now identified a new lead compound, SR18662. We find that treatment with SR18662 significantly reduces growth and proliferation of colorectal cancer cells as compared with treatment with vehicle control, ML264, or SR15006 (a less optimized analogue from SAR efforts leading to SR18662). SR18662 showed improved efficacy in reducing the viability of multiple colorectal cancer cell lines. Flow cytometry analysis following SR18662 treatment showed an increase in cells captured in either S or G2-M phases of the cell cycle and a significant increase in the number of apoptotic cells, the latter a unique property compared with ML264 or SR15006. SR18662 treatment also reduces the expression of cyclins and components of the MAPK and WNT signaling pathways. Importantly, we observed a significant dose-dependent inhibition of xenograft growth in mice following SR18662 treatment that exceeded the effect of ML264 at equivalent doses. These findings support further development of SR18662 and its analogues for colorectal cancer therapy.

10.
J Clin Invest ; 129(8): 3103-3120, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31112137

RESUMO

Mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) are yet unclear. Specific deletion of the ER-component membralin in astrocytes manifested postnatal motor defects and lethality in mice, causing the accumulation of extracellular glutamate through reducing the glutamate transporter EAAT2. Restoring EAAT2 levels in membralin KO astrocytes limited astrocyte-dependent excitotoxicity in motor neurons. Transcriptomic profiles from mouse astrocytic membralin KO motor cortex indicated significant perturbation in KEGG pathway components related to ALS, including downregulation of Eaat2 and upregulation of Tnfrsf1a. Changes in gene expression with membralin deletion also overlapped with mouse ALS models and reactive astrocytes. Our results shown that activation of TNF receptor (TNFR1)-NFκB pathway known to suppress Eaat2 transcription was upregulated with membralin deletion. Further, reduced membralin and EAAT2 levels correlated with disease progression in spinal cord from SOD1-mutant mouse models, and reductions in membralin/EAAT2 were observed in human ALS spinal cord. Importantly, overexpression of membralin in SOD1G93A astrocytes decreased TNFR1 levels and increased EAAT2 expression, and improved motor neuron survival. Importantly, upregulation of membralin in SOD1G93A mice significantly prolonged mouse survival. Together, our study provided a mechanism for ALS pathogenesis where membralin limited glutamatergic neurotoxicity, suggesting that modulating membralin had potentials in ALS therapy.

11.
Sci Rep ; 9(1): 4424, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30872623

RESUMO

One of the fossil record's most puzzling features is the absence of preserved eggs or eggshell for the first third of the known 315 million year history of amniote evolution. Our meagre understanding of the origin and evolution of calcareous eggshell and amniotic eggs in general, is largely based on Middle Jurassic to Late Cretaceous fossils. For dinosaurs, the most parsimonious inference yields a thick, hard shelled egg, so richly represented in the Late Cretaceous fossil record. Here, we show that a thin calcareous layer (≤100 µm) with interlocking units of radiating crystals (mammillae) and a thick shell membrane already characterize the oldest known amniote eggs, belonging to three coeval, but widely distributed Early Jurassic basal sauropodomorph dinosaurs. This thin shell layer strongly contrasts with the considerably thicker calcareous shells of Late Jurassic dinosaurs. Phylogenetic analyses and their Sinemurian age indicate that the thin eggshell of basal sauropodomorphs represents a major evolutionary innovation at the base of Dinosauria and that the much thicker eggshell of sauropods, theropods, and ornithischian dinosaurs evolved independently. Advanced mineralization of amniote eggshell (≥150 µm in thickness) in general occurred not earlier than Middle Jurassic and may correspond with a global trend of increase in atmospheric oxygen.

12.
ACS Chem Neurosci ; 10(2): 828-838, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30261139

RESUMO

Alzheimer's disease (AD) comprises two major pathological hallmarks: extraneuronal deposition of ß-amyloid (Aß) peptides ("senile plaques") and intraneuronal aggregation of the microtubule-associated protein tau ("neurofibrillary tangles"). Aß is derived from sequential cleavage of the ß-amyloid precursor protein by ß- and γ-secretases, while aggregated tau is hyperphosphorylated in AD. Mounting evidence suggests that dysregulated trafficking of these AD-related proteins contributes to AD pathogenesis. Rab proteins are small GTPases that function as master regulators of vesicular transport and membrane trafficking. Multiple Rab GTPases have been implicated in AD-related protein trafficking, and their expression has been observed to be altered in postmortem AD brain. Here we review current implicated roles of Rab GTPase dysregulation in AD pathogenesis. Further elucidation of the pathophysiological role of Rab GTPases will likely reveal novel targets for AD therapeutics.

13.
Biol Psychiatry ; 86(3): 171-184, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30292394

RESUMO

BACKGROUND: Although synaptic impairment is a prerequisite to cognitive deficiencies in Alzheimer's disease (AD), mechanisms underlying the dysregulation of essential synaptic scaffolding components and their integrity remain elusive. RPS23RG1 is a newly identified protein implicated in AD. However, the physiological function of RPS23RG1 has yet to be determined. METHODS: We investigated the role of RPS23RG1 in maintaining synaptic structure and function in cell cultures and in Rps23rg1 knockout mice and determined whether targeting RPS23RG1-mediated pathways has therapeutic potential in APP/PS1 AD model mice. RESULTS: Deletion of the Rps23rg1 gene resulted in severe memory deficits and impairment of postsynaptic structure and function, with marked reductions in postsynaptic densities-93 and -95 (PSD-93 and PSD-95) levels. RPS23RG1 interacted with PSD-93/PSD-95 through its intracellular domain, consequently sequestering PSD-93/PSD-95 from murine double minute 2-mediated ubiquitination and degradation, thereby maintaining synaptic function. Restoration of PSD-93/PS-D95 levels reversed synaptic and memory deficits in Rps23rg1 knockout mice. We further observed attenuated RPS23RG1 expression in human AD, which positively correlated with PSD-93/PSD-95 levels. Importantly, an RPS23RG1-derived peptide comprising a unique PSD-93/PSD-95 interaction motif rescued synaptic and cognitive defects in Rps23rg1 knockout and AD mouse models. CONCLUSIONS: Our results reveal a role for RPS23RG1 in maintaining synaptic integrity and function and provide a new mechanism for synaptic dysfunction in AD pathogenesis. This demonstrates that RPS23RG1-mediated pathways show good therapeutic potential in AD intervention.

14.
Biol Psychiatry ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31955914

RESUMO

BACKGROUND: Synaptic protein dyshomeostasis and functional loss is an early invariant feature of Alzheimer's disease (AD), yet the unifying etiological pathway remains largely unknown. Knowing that cyclin-dependent kinase 5 (CDK5) plays critical roles in synaptic formation and degeneration, its phosphorylation targets were reexamined in search of candidates with direct global impacts on synaptic protein dynamics, and the associated regulatory network was also analyzed. METHODS: Quantitative phosphoproteomics and bioinformatics analyses were performed to identify top-ranked candidates. A series of biochemical assays was used to investigate the associated regulatory signaling networks. Histological, electrochemical, and behavioral assays were performed in conditional knockout, small hairpin RNA-mediated knockdown, and AD-related mice models to evaluate the relevance of CDK5 to synaptic homeostasis and functions. RESULTS: Among candidates with known implications in synaptic modulations, BAG3 ranked the highest. CDK5-mediated phosphorylation on S297/S291 (mouse/human) destabilized BAG3. Loss of BAG3 unleashed the selective protein degradative function of the HSP70 machinery. In neurons, this resulted in enhanced degradation of a number of glutamatergic synaptic proteins. Conditional neuronal knockout of Bag3 in vivo led to impairment of learning and memory functions. In human AD and related mouse models, aberrant CDK5-mediated loss of BAG3 yielded similar effects on synaptic homeostasis. Detrimental effects of BAG3 loss on learning and memory functions were confirmed in these mice, and such effects were reversed by ectopic BAG3 reexpression. CONCLUSIONS: Our results highlight that the neuronal CDK5-BAG3-HSP70 signaling axis plays a critical role in modulating synaptic homeostasis. Dysregulation of the signaling pathway directly contributes to synaptic dysfunction and AD pathogenesis.

15.
PLoS One ; 13(11): e0205206, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30403689

RESUMO

The great diversity of dinosaurian tooth shapes and sizes, and in particular, the amazing dental complexity in derived ornithischians has attracted a lot of attention. However, the evolution of dental batteries in hadrosaurids and ceratopsids is difficult to understand without a broader comparative framework. Here we describe tooth histology and development in the "middle" Cretaceous ornithischian dinosaur Changchunsaurus parvus, a small herbivore that has been characterized as an early ornithopod, or even as a more basal ornithischian. We use this taxon to show how a "typical" ornithischian dentition develops, copes with wear, and undergoes tooth replacement. Although in most respects the histological properties of their teeth are similar to those of other dinosaurs, we show that, as in other more derived ornithischians, in C. parvus the pulp chamber is not invaded fully by the newly developing replacement tooth until eruption is nearly complete. This allowed C. parvus to maintain an uninterrupted shearing surface along a single tooth row, while undergoing continuous tooth replacement. Our histological sections also show that the replacement foramina on the lingual surfaces of the jaws are likely the entry points for an externally placed dental lamina, a feature found in many other ornithischian dinosaurs. Surprisingly, our histological analysis also revealed the presence of wavy enamel, the phylogenetically earliest occurrence of this type of tissue. This contradicts previous interpretations that this peculiar type of enamel arose in association with more complex hadrosauroid dentitions. In view of its early appearance, we suggest that wavy enamel may have evolved in association with a shearing-type dentition in a roughly symmetrically-enameled crown, although its precise function still remains somewhat of a mystery.


Assuntos
Amelogênese , Dinossauros , Fósseis , Odontogênese , Dente , Animais , Esmalte Dentário/citologia , Esmalte Dentário/ultraestrutura , Dinossauros/anatomia & histologia , Dente/citologia , Dente/crescimento & desenvolvimento , Dente/ultraestrutura
16.
Neuron ; 100(3): 551-563.e7, 2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30220511

RESUMO

Astrocyte dysfunction and inflammation are associated with the pathogenesis of major depressive disorder (MDD). However, the mechanisms underlying these effects remain largely unknown. Here, we found that multiple endocrine neoplasia type 1 (Men1; protein: menin) expression is attenuated in the brain of mice exposed to CUMS (chronic unpredictable mild stress) or lipopolysaccharide. Astrocyte-specific reduction of Men1 (GcKO) led to depressive-like behaviors in mice. We observed enhanced NF-κB activation and IL-1ß production with menin deficiency in astrocytes, where depressive-like behaviors in GcKO mice were restored by NF-κB inhibitor or IL-1ß receptor antagonist. Importantly, we identified a SNP, rs375804228, in human MEN1, where G503D substitution is associated with a higher risk of MDD onset. G503D substitution abolished menin-p65 interactions, thereby enhancing NF-κB activation and IL-1ß production. Our results reveal a distinct astroglial role for menin in regulating neuroinflammation in depression, indicating that menin may be an attractive therapeutic target in MDD.


Assuntos
Astrócitos/metabolismo , Transtorno Depressivo Maior/metabolismo , Proteínas Proto-Oncogênicas/deficiência , Estresse Psicológico/metabolismo , Adulto , Animais , Astrócitos/patologia , Células Cultivadas , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/psicologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/genética , Estresse Psicológico/genética , Estresse Psicológico/psicologia
17.
Cell Rep ; 24(3): 701-712, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-30021166

RESUMO

Menin (MEN1) is a critical modulator of tissue development and maintenance. As such, MEN1 mutations are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. Although menin is abundantly expressed in the nervous system, little is known with regard to its function in the adult brain. Here, we demonstrate that neuron-specific deletion of Men1 (CcKO) affects dendritic branching and spine formation, resulting in defects in synaptic function, learning, and memory. Furthermore, we find that menin binds to the p35 promoter region to facilitate p35 transcription. As a primary Cdk5 activator, p35 is expressed mainly in neurons and is critical for brain development and synaptic plasticity. Restoration of p35 expression in the hippocampus and cortex of Men1 CcKO mice rescues synaptic and cognitive deficits associated with Men1 deletion. These results reveal a critical role for menin in synaptic and cognitive function by modulating the p35-Cdk5 pathway.


Assuntos
Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Neurônios/metabolismo , Fosfotransferases/genética , Proteínas Proto-Oncogênicas/deficiência , Sinapses/metabolismo , Animais , Disfunção Cognitiva/complicações , Regulação da Expressão Gênica , Loci Gênicos , Transtornos da Memória/complicações , Transtornos da Memória/fisiopatologia , Camundongos Knockout , Especificidade de Órgãos , Fosfotransferases/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas/metabolismo , Sinapses/patologia , Transcrição Genética
18.
J Exp Med ; 215(6): 1665-1677, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29739836

RESUMO

ß-amyloid protein (Aß) plays a central role in the pathogenesis of Alzheimer disease (AD). Aß is generated from sequential cleavage of amyloid precursor protein (APP) by ß-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. Although activation of some protein kinase C (PKC) isoforms such as PKCα and ε has been shown to regulate nonamyloidogenic pathways and Aß degradation, it is unclear whether other PKC isoforms are involved in APP processing/AD pathogenesis. In this study, we report that increased PKCδ levels correlate with BACE1 expression in the AD brain. PKCδ knockdown reduces BACE1 expression, BACE1-mediated APP processing, and Aß production. Conversely, overexpression of PKCδ increases BACE1 expression and Aß generation. Importantly, inhibition of PKCδ by rottlerin markedly reduces BACE1 expression, Aß levels, and neuritic plaque formation and rescues cognitive deficits in an APP Swedish mutations K594N/M595L/presenilin-1 with an exon 9 deletion-transgenic AD mouse model. Our study indicates that PKCδ plays an important role in aggravating AD pathogenesis, and PKCδ may be a potential target in AD therapeutics.


Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Proteína Quinase C-delta/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Acetofenonas/farmacologia , Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Benzopiranos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/patologia , Linhagem Celular , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Humanos , Camundongos Transgênicos , Inibidor de NF-kappaB alfa/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fenótipo , Fosforilação/efeitos dos fármacos , Proteína Quinase C-delta/metabolismo , Subunidades Proteicas/metabolismo , RNA Interferente Pequeno/metabolismo , Regulação para Cima/efeitos dos fármacos
19.
Front Aging Neurosci ; 10: 79, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29632483

RESUMO

The retromer complex and associated sorting nexins (SNXs) comprise a critical trafficking machinery which mediates endosomal protein sorting. Retromer and/or SNX dysfunction has been linked to several neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Down's syndrome (DS). In AD, deficiency of the retromer complex or its cargo proteins impairs endosomal trafficking of amyloid precursor protein (APP), resulting in the overproduction of ß-amyloid (Aß). Several SNX components directly interact with APP or APP-cleaving enzymes (ß- and γ-secretases) to regulate amyloidogenic APP processing and Aß generation. In addition, PD-linked mutations in retromer components cause mistrafficking of retromer cargo proteins and mitochondrial dysfunction, and dysregulation retromer-mediated trafficking has been considered as an important cause of hereditary spastic paraplegia (HSP) and neuronal ceroid lipofuscinoses (NCLs). Moreover, SNX27 deficiency is an important contributor for synaptic and cognitive impairment in DS. Here we review recent findings describing the retromer complex and/or SNXs-mediated endosomal sorting in neurodegenerative disorders.

20.
Neuron ; 97(5): 1023-1031.e7, 2018 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-29518356

RESUMO

Mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to increased Alzheimer's disease (AD) risk. Neurobiological functions of TREM2 and its pathophysiological ligands remain elusive. Here we found that TREM2 directly binds to ß-amyloid (Aß) oligomers with nanomolar affinity, whereas AD-associated TREM2 mutations reduce Aß binding. TREM2 deficiency impairs Aß degradation in primary microglial culture and mouse brain. Aß-induced microglial depolarization, K+ inward current induction, cytokine expression and secretion, migration, proliferation, apoptosis, and morphological changes are dependent on TREM2. In addition, TREM2 interaction with its signaling adaptor DAP12 is enhanced by Aß, regulating downstream phosphorylation of SYK and GSK3ß. Our data demonstrate TREM2 as a microglial Aß receptor transducing physiological and AD-related pathological effects associated with Aß.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Glicoproteínas de Membrana/metabolismo , Microglia/fisiologia , Receptores Imunológicos/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Células Cultivadas , Método Duplo-Cego , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microglia/patologia , Ligação Proteica/fisiologia
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