RESUMO
Dysfunction of the ubiquitin-proteasome system has recently been implicated in the pathogenesis of some untreatable myodegenerative diseases characterized by the formation of ubiquitinated inclusions in skeletal muscles. We have developed an in vitro model of proteasomal dysfunction by applying inhibitors of the proteasome to primary adult human skeletal muscle cultures. Our data show that proteasome inhibition causes both cytoplasmic accumulation of ubiquitinated inclusions and apoptotic death, the latter through accumulation of active caspase-3.
Assuntos
Apoptose/efeitos dos fármacos , Leupeptinas/farmacologia , Mioblastos/efeitos dos fármacos , Inibidores de Proteassoma , Adulto , Antineoplásicos/farmacologia , Caspase 3/metabolismo , Sobrevivência Celular , Células Cultivadas , Humanos , Corpos de Inclusão/química , Corpos de Inclusão/metabolismo , Modelos Biológicos , Mioblastos/citologia , Mioblastos/metabolismo , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Ubiquitina/metabolismoRESUMO
BACKGROUND: Mutations in the progranulin gene (PGRN) were identified as the causal mechanism underlying frontotemporal lobar degeneration (FTLD). Most of these mutations are predicted to create null alleles leading to a 50% loss of progranulin transcript. METHODS: Patients underwent clinical and neurologic examination at the Memory Clinic of the IRCCS S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy. We enrolled affected (n = 6) and unaffected at risk members (n = 73) of families carrying the FTLD associated progranulin Leu271LeufsX10 mutation; additionally, we included subjects affected by sporadic/familial FTLD (n = 65), controls (n = 75), and a family carrying the tau P301L mutation. The presence of mutations in PGRN and MAPT genes was investigated by direct sequencing of exonic and flanking intronic regions. Progranulin plasma and CSF levels were measured using ELISA. RESULTS: We demonstrated that progranulin protein is strongly reduced (up to 3.93-fold) both in plasma and CSF of affected and unaffected subjects carrying mutations in progranulin gene (PGRN Leu271LeufsX10 and Q341X). We established a plasma progranulin protein cutoff level of 74.4 ng/mL that identifies, with specificity and sensitivity of 100%, mutation carriers among unaffected subjects. In FTLD, values Assuntos
Demência/sangue
, Demência/genética
, Peptídeos e Proteínas de Sinalização Intercelular/sangue
, Peptídeos e Proteínas de Sinalização Intercelular/genética
, Adulto
, Idoso
, Análise Mutacional de DNA
, Demência/líquido cefalorraquidiano
, Humanos
, Peptídeos e Proteínas de Sinalização Intercelular/líquido cefalorraquidiano
, Masculino
, Pessoa de Meia-Idade
, Mutação
, Linhagem
, Progranulinas
RESUMO
Growing evidence advanced the idea that the soluble form of the receptor for advanced glycation end-products (sRAGE) might serve as a risk marker for several disorders including Alzheimer disease. We found a reduced level of circulating sRAGE in patients with mild cognitive impairment (MCI). The reduction of sRAGE in MCI, as well as the anticipation of the disease in patients with the lowest sRAGE levels (Assuntos
Transtornos Cognitivos/sangue
, Receptores Imunológicos/sangue
, Idade de Início
, Idoso
, Estudos de Casos e Controles
, Feminino
, Humanos
, Masculino
, Receptor para Produtos Finais de Glicação Avançada
, Estatística como Assunto