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1.
Klin Padiatr ; 233(6): 267-277, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34407551

RESUMO

Children with Down syndrome are at a high risk of developing transient abnormal myelopoiesis (TAM; synonym: TMD) or myeloid leukemia (ML-DS). While most patients with TAM are asymptomatic and go into spontaneous remission without a need for therapy, around 20% of patients die within the first six months due to TAM-related complications. Another 20-30% of patients progress from TAM to ML-DS. ML-DS patients are particularly vulnerable to therapy-associated toxicity, but the prognosis of relapsed ML-DS is extremely poor - thus, ML-DS therapy schemata must strive for a balance between appropriate efficacy (to avoid relapses) and treatment-related toxicity. This guideline presents diagnostic and therapeutic strategies for TAM and ML-DS based on the experience and results of previous clinical studies from the BFM working group, which have helped reduce the risk of early death in symptomatic TAM patients using low-dose cytarabine, and which have achieved excellent cure rates for ML-DS using intensity-reduced treatment protocols.


Assuntos
Síndrome de Down , Leucemia Mieloide , Reação Leucemoide , Criança , Síndrome de Down/diagnóstico , Síndrome de Down/terapia , Fator de Transcrição GATA1/genética , Humanos , Reação Leucemoide/diagnóstico , Reação Leucemoide/terapia
2.
J Biol Chem ; 291(16): 8805-15, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26903513

RESUMO

The supply of MHC class I-restricted peptides is primarily ensured by the degradation of intracellular proteins via the ubiquitin-proteasome system. Depending on the target and the enzymes involved, ubiquitination is a process that may dramatically vary in terms of linkages, length, and attachment sites. Here we identified the unique lysine residue at position 124 of the NY-ESO-1 cancer/testis antigen as the acceptor site for the formation of canonical Lys-48-linkages. Interestingly, a lysine-less form of NY-ESO-1 was as efficient as its wild-type counterpart in supplying the HLA-A*0201-restricted NY-ESO-1157-165 antigenic peptide. In fact, we show that the regulation of NY-ESO-1 processing by the ubiquitin receptors Rpn10 and Rpn13 as a well as by the standard and immunoproteasome is governed by non-canonical ubiquitination on non-lysine sites. In summary, our data underscore the significance of atypical ubiquitination in the modulation of MHC class I antigen processing.


Assuntos
Apresentação de Antígeno , Antígenos de Neoplasias/imunologia , Antígeno HLA-A2/imunologia , Glicoproteínas de Membrana/imunologia , Proteínas de Membrana/imunologia , Complexo de Endopeptidases do Proteassoma/imunologia , Ubiquitinação/imunologia , Antígenos de Neoplasias/genética , Antígeno HLA-A2/genética , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Complexo de Endopeptidases do Proteassoma/genética , Proteínas de Ligação a RNA , Ubiquitinação/genética
3.
medRxiv ; 2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38293138

RESUMO

Neurodevelopmental proteasomopathies represent a distinctive category of neurodevelopmental disorders (NDD) characterized by genetic variations within the 26S proteasome, a protein complex governing eukaryotic cellular protein homeostasis. In our comprehensive study, we identified 23 unique variants in PSMC5 , which encodes the AAA-ATPase proteasome subunit PSMC5/Rpt6, causing syndromic NDD in 38 unrelated individuals. Overexpression of PSMC5 variants altered human hippocampal neuron morphology, while PSMC5 knockdown led to impaired reversal learning in flies and loss of excitatory synapses in rat hippocampal neurons. PSMC5 loss-of-function resulted in abnormal protein aggregation, profoundly impacting innate immune signaling, mitophagy rates, and lipid metabolism in affected individuals. Importantly, targeting key components of the integrated stress response, such as PKR and GCN2 kinases, ameliorated immune dysregulations in cells from affected individuals. These findings significantly advance our understanding of the molecular mechanisms underlying neurodevelopmental proteasomopathies, provide links to research in neurodegenerative diseases, and open up potential therapeutic avenues.

4.
Sci Transl Med ; 15(698): eabo3189, 2023 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-37256937

RESUMO

A critical step in preserving protein homeostasis is the recognition, binding, unfolding, and translocation of protein substrates by six AAA-ATPase proteasome subunits (ATPase-associated with various cellular activities) termed PSMC1-6, which are required for degradation of proteins by 26S proteasomes. Here, we identified 15 de novo missense variants in the PSMC3 gene encoding the AAA-ATPase proteasome subunit PSMC3/Rpt5 in 23 unrelated heterozygous patients with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Expression of PSMC3 variants in mouse neuronal cultures led to altered dendrite development, and deletion of the PSMC3 fly ortholog Rpt5 impaired reversal learning capabilities in fruit flies. Structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune programs. The proteostatic perturbations in T cells from patients with PSMC3 variants correlated with a dysregulation in type I interferon (IFN) signaling in these T cells, which could be blocked by inhibition of the intracellular stress sensor protein kinase R (PKR). These results suggest that proteotoxic stress activated PKR in patient-derived T cells, resulting in a type I IFN response. The potential relationship among proteosome dysfunction, type I IFN production, and neurodevelopment suggests new directions in our understanding of pathogenesis in some neurodevelopmental disorders.


Assuntos
Interferon Tipo I , Complexo de Endopeptidases do Proteassoma , Animais , Humanos , Camundongos , Adenosina Trifosfatases/genética , Drosophila melanogaster , Expressão Gênica , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteômica
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