Inactivation of CDK/pRb Pathway Normalizes Survival Pattern of Lymphoblasts Expressing the FTLD-Progranulin Mutation c.709-1G>A

8 figuras, 2 tablasBackground 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. Methodology/Principal Findings 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. Conclusion/Significance 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-TDPThis work has been supported by grants from Ministry of Education and Science (SAF2007-61701, SAF2010-15700, SAF2011-28603), Fundación Eugenio Rodríguez Pascual, and Basque Government (Saiotek program 2008–2009). NE holds a fellowship of the JAE predoctoral program of the CSICPeer reviewe

Association of genetic variations in the mitochondrial DNA control region with presbycusis

Masoumeh Falah,1 Mohammad Farhadi,1 Seyed Kamran Kamrava,1 Saeid Mahmoudian,1 Ahmad Daneshi,1 Maryam Balali,1 Alimohamad Asghari,2 Massoud Houshmand1,3 1ENT and Head & Neck Research Center and Department, Iran University of Medical Sciences, Tehran, Iran; 2Skull Base Research Center, Iran University of Medical Sciences, Tehran, Iran; 3Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran Background: The prominent role of mitochondria in the generation of reactive oxygen species, cell death, and energy production contributes to the importance of this organelle in the intracellular mechanism underlying the progression of the common sensory disorder of the elderly, presbycusis. Reduced mitochondrial DNA (mtDNA) gene expression and coding region variation have frequently been reported as being associated with the development of presbycusis. The mtDNA control region regulates gene expression and replication of the genome of this organelle. To comprehensively understand of the role of mitochondria in the progression of presbycusis, we compared variations in the mtDNA control region between subjects with presbycusis and controls.Methods: A total of 58 presbycusis patients and 220 control subjects were enrolled in the study after examination by the otolaryngologist and audiology tests. Variations in the mtDNA control region were investigated by polymerase chain reaction and Sanger sequencing.Results: A total of 113 sequence variants were observed in mtDNA, and variants were detected in 100% of patients, with 84% located in hypervariable regions. The frequencies of the variants, 16,223 C>T, 16,311 T>C, 16,249 T>C, and 15,954 A>C, were significantly different between presbycusis and control subjects.Conclusion: The statistically significant difference in the frequencies of four nucleotide variants in the mtDNA control region of presbycusis patients and controls is in agreement with previous experimental evidence and supports the role of mitochondria in the intracellular mechanism underlying presbycusis development. Moreover, these variants have potential as diagnostic markers for individuals at a high risk of developing presbycusis. The data also suggest the possible presence of changes in the mtDNA control region in presbycusis, which could alter regulatory factor binding sites and influence mtDNA gene expression and copy number. Keywords: age-related hearing impairment, presbycusis, mtDNA control region, audiolog

Global Study of Variability in Olfactory Sensitivity

Variability in human olfactory sensitivity has been attributed to individual-level factors such as genetics, age, sex, medical history of infections and trauma, neurogenerative diseases, and emotional disorders. Scarce evidence exists on the cross-cultural variation in olfactory sensitivity. Hence, we performed 2 studies to estimate the variability in olfactory threshold as a function of location and environment. Study 1 involved 11 laboratories from 4 continents (N 802). In each location, in a designated laboratory, approximately 80 subjects underwent olfactory sensitivity testing with custom-made tests with eucalyptol and phenylethanol (PEA) odors. Tests were based on the Threshold subtest of the Sniffin’ Sticks battery. In Study 2, we compared olfactory sensitivity and suprathreshold perception of PEA and eucalyptol in 2 Chinese (N = 160) and 2 Indian (N = 92) populations—one based in their native country and the other in Germany. Both studies present large-scale evidence that olfactory sensitivity varies as a function of geographical location and suggest that environmental factors play an important role in shaping olfactory sensitivity and suprathreshold olfactory perception. We delineate further steps necessary to identify specific factors underlying uncovered variability and the relationship between olfactory sensitivity and suprathreshold odor perception