title: Inactivation of CDK/pRb pathway normalizes survival pattern of lymphoblasts expressing the FTLD-progranulin mutation c.709-1G>A.
abstract: BACKGROUND
  Mutations in the progranulin (PGRN) gene, leading to haploinsufficiency, cause familial frontotemporal lobar degeneration (FTLD-TDP), although the pathogenic mechanism of PGRN deficit is largely unknown. Allelic loss of PGRN was previously shown to increase the activity of cyclin-dependent kinase (CDK) CDK6/pRb pathway in lymphoblasts expressing the c.709-1G>A PGRN mutation. Since members of the CDK family appear to play a role in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults, we investigated the role of CDK6/pRb in cell survival/death mechanisms following serum deprivation.
  
  
  RESULTS
  We performed a comparative study of cell viability after serum withdrawal of established lymphoblastoid cell lines from control and carriers of c.709-1G>A PGRN mutation, asymptomatic and FTLD-TDP diagnosed individuals. Our results suggest that the CDK6/pRb pathway is enhanced in the c.709-1G>A bearing lymphoblasts. Apparently, this feature allows PGRN-deficient cells to escape from serum withdrawal-induced apoptosis by decreasing the activity of executive caspases and lowering the dissipation of mitochondrial membrane potential and the release of cytochrome c from the mitochondria. Inhibitors of CDK6 expression levels like sodium butyrate or the CDK6 activity such as PD332991 were able to restore the vulnerability of lymphoblasts from FTLD-TDP patients to trophic factor withdrawal.
  
  
  CONCLUSIONS
  The use of PGRN-deficient lymphoblasts from FTLD-TDP patients may be a useful model to investigate cell biochemical aspects of this disease. It is suggested that CDK6 could be potentially a therapeutic target for the treatment of the FTLD-TDP.
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Alquezar
authors.forename: Noemí
authors.initials: N
authors.lastname: Esteras
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Alzualde
authors.forename: Fermín
authors.initials: F
authors.lastname: Moreno
authors.forename: Matilde S
authors.initials: MS
authors.lastname: Ayuso
authors.forename: Adolfo
authors.initials: A
authors.lastname: López de Munain
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Martín-Requero
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D017209:Apoptosis / Q000502:physiology; D002470:Cell Survival / Q000502:physiology*; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics*; D005260:Female; D005453:Fluorescence; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D008214:Lymphocytes / Q000502:physiology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008875:Middle Aged; D017354:Point Mutation / Q000235:genetics; D000077153:Progranulins; D044967:Serum / Q000502:physiology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6