Spitz tumors are melanocytic neoplasms characterized by specific, mutually exclusive driver molecular events, namely genomic rearrangements involving the threonine kinase BRAF and the tyrosine kinase receptors ALK , NTRK1 , NTRK2 , NTRK3 , MET , RET , ROS1 , and MAP3K8 or less commonly, mutations in HRAS or MAP2K1 . We hereby report 5 Spitz tumors with a SQSTM1::NTRK2 fusion. All patients were woman with the ages at diagnosis ranging from 30 to 50 years. Locations included the lower extremity (n = 3), forearm, and back (one each). All the neoplasms were superficial melanocytic proliferation with a flat to dome-shaped silhouette, in which junctional spindled and polygonal dendritic melanocytes were mainly arranged as horizontal nests associated with conspicuous lentiginous involvement of the follicular epithelium. Only one case showed heavily pigmented, vertically oriented melanocytic nests resembling Reed nevus. A superficial intradermal component observed in 2 cases appeared as small nests with a back-to-back configuration. In all lesions, next-generation sequencing analysis identified a SQSTM1::NTRK2 fusion. A single case studied with fluorescence in situ hybridization for copy number changes in melanoma-related genes proved negative. No further molecular alterations were detected, including TERT-p hotspot mutations.

• MeSH
• dospělí MeSH
• epiteloidní a vřetenobuněčný névus * genetika   MeSH
• hybridizace in situ fluorescenční MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory kůže * patologie   MeSH
• protoonkogenní proteiny genetika   MeSH
• sekvestosom 1 genetika   MeSH
• tyrosinkinasové receptory genetika   MeSH
• tyrosinkinasy genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Bidirectional interactions between astrocytes and neurons have physiological roles in the central nervous system and an altered state or dysfunction of such interactions may be associated with neurodegenerative diseases, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Astrocytes exert structural, metabolic and functional effects on neurons, which can be either neurotoxic or neuroprotective. Their neurotoxic effect is mediated via the senescence-associated secretory phenotype (SASP) involving pro-inflammatory cytokines (e.g., IL-6), while their neuroprotective effect is attributed to neurotrophic growth factors (e.g., NGF). We here demonstrate that the p53 isoforms Δ133p53 and p53β are expressed in astrocytes and regulate their toxic and protective effects on neurons. Primary human astrocytes undergoing cellular senescence upon serial passaging in vitro showed diminished expression of Δ133p53 and increased p53β, which were attributed to the autophagic degradation and the SRSF3-mediated alternative RNA splicing, respectively. Early-passage astrocytes with Δ133p53 knockdown or p53β overexpression were induced to show SASP and to exert neurotoxicity in co-culture with neurons. Restored expression of Δ133p53 in near-senescent, otherwise neurotoxic astrocytes conferred them with neuroprotective activity through repression of SASP and induction of neurotrophic growth factors. Brain tissues from AD and ALS patients possessed increased numbers of senescent astrocytes and, like senescent astrocytes in vitro, showed decreased Δ133p53 and increased p53β expression, supporting that our in vitro findings recapitulate in vivo pathology of these neurodegenerative diseases. Our finding that Δ133p53 enhances the neuroprotective function of aged and senescent astrocytes suggests that the p53 isoforms and their regulatory mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases.

• MeSH
• alternativní sestřih MeSH
• Alzheimerova nemoc metabolismus   patologie   MeSH
• amyotrofická laterální skleróza metabolismus   patologie   MeSH
• astrocyty cytologie   účinky léků   metabolismus   MeSH
• autofagie účinky léků   MeSH
• genetické vektory genetika   metabolismus   MeSH
• interleukin-6 genetika   metabolismus   MeSH
• kokultivační techniky MeSH
• kultivované buňky MeSH
• leupeptiny farmakologie   MeSH
• lidé MeSH
• malá interferující RNA metabolismus   MeSH
• mozek metabolismus   patologie   MeSH
• nádorový supresorový protein p53 antagonisté a inhibitory   genetika   metabolismus   MeSH
• neurony cytologie   metabolismus   MeSH
• neuroprotekce fyziologie   MeSH
• protein - isoformy antagonisté a inhibitory   genetika   metabolismus   MeSH
• RNA interference MeSH
• sekvestosom 1 antagonisté a inhibitory   genetika   metabolismus   MeSH
• serin-arginin sestřihové faktory antagonisté a inhibitory   genetika   metabolismus   MeSH
• stárnutí buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.

• MeSH
• adaptorové proteiny signální transdukční * genetika   MeSH
• amyotrofická laterální skleróza MeSH
• DNA vazebné proteiny genetika   MeSH
• dospělí MeSH
• frontotemporální lobární degenerace * genetika   patologie   MeSH
• genetická predispozice k nemoci * genetika   MeSH
• jednonukleotidový polymorfismus * genetika   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• metaanalýza jako téma MeSH
• mezinárodní spolupráce MeSH
• mutační analýza DNA MeSH
• sekvestosom 1 MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH