Search result for : author:olaf ansorge

Total 3 result(s) found

Frequency and signature of somatic variants in 1461 human brain exomes.

To systematically study somatic variants arising during development in the human brain across a spectrum of neurodegenerative disorders. In this study we developed a pipeline to identify somatic variants from exome sequencing data in 1461 diseased and control human brains. Eighty-eight percent of the DNA samples were extracted from the cerebellum. Identified somatic variants were validated by targeted amplicon sequencing and/or PyroMark® Q24. We observed somatic coding variants present in >10% of sampled cells in at least 1% of brains. The mutational signature of the detected variants showed a predominance of C>T variants most consistent with arising from DNA mismatch repair, occurred frequently in genes that are highly expressed within the central nervous system, and with a minimum somatic mutation rate of 4.25 × 10 per base pair per individual. These findings provide proof-of-principle that deleterious somatic variants can affect sizeable brain regions in at least 1% of the population, and thus have the potential to contribute to the pathogenesis of common neurodegenerative diseases.

Wei Wei, Michael J Keogh, Juvid Aryaman, Zoe Golder, Peter J Kullar, Ian Wilson, Kevin Talbot, Martin R Turner, Chris-Anne McKenzie, Claire Troakes, Johannes Attems, Colin Smith, Safa Al Sarraj, Chris M Morris, Olaf Ansorge, Nick S Jones, James W Ironside

Neuronal intranuclear inclusions in SCA2: a genetic, morphological and immunohistochemical study of two cases.

Spinocerebellar ataxia 2 (SCA2) belongs to the family of autosomal dominant cerebellar ataxias (ADCA), a genetically heterogeneous group of neurodegenerative diseases. The SCA2 gene maps to chromosome 12q24 and the causative mutation involves the expansion of a CAG repeat within the coding region of the gene. Pathologically, SCA2 presents as olivo-ponto-cerebellar atrophy (OPCA). We present the cases of a 41-year-old man and a 54-year-old woman who died after a long illness characterized by severe cerebellar ataxia. Diagnosis of SCA2 was confirmed by genetic analysis. The brains were moderately to severely atrophic and atrophy was particularly obvious in the cerebellum and brainstem. Histological examination revealed extreme loss of pontine and olivary nuclei and Purkinje cells, with preservation of the dentate nuclei, and of the pigmented cells in the substantia nigra. The whole spinal cord was also severely affected, with shrinkage of the dorsal columns and reduction in the number of neurones in the motor pool and Clarke's nuclei. Immunohistochemistry with 1C2 antibody showed granular neuronal cytoplasmic deposits in all the areas examined and widespread intranuclear inclusions, which were particularly numerous in the residual pontine nuclei. Intranuclear inclusions were not considered a feature in SCA2. Our results support the view that intranuclear inclusions are an integral part of the pathology of this mutation.

Joanna T Pang, Paola Giunti, Susan Chamberlain, Shu F An, Roberta Vitaliani, Tomaso Scaravilli, Lillian Martinian, Nicholas W Wood, Francesco Scaravilli, Olaf Ansorge

Functional expression of calcium-permeable canonical transient receptor potential 4-containing channels promotes migration of medulloblastoma cells.

The proton sensing ovarian cancer G protein coupled receptor 1 (OGR1, aka GPR68) promotes expression of the canonical transient receptor potential channel subunit TRPC4 in normal and transformed cerebellar granule precursor (DAOY) cells. OGR1 and TRPC4 are prominently expressed in healthy cerebellar tissue throughout postnatal development and in primary cerebellar medulloblastoma tissues. Activation of TRPC4-containing channels in DAOY cells, but not non-transformed granule precursor cells, results in prominent increases in [Ca ] and promotes cell motility in wound healing and transwell migration assays. Medulloblastoma cells not arising from granule precursor cells show neither prominent rises in [Ca ] nor enhanced motility in response to TRPC4 activation unless they overexpressTRPC4. Our results suggest that OGR1 enhances expression of TRPC4-containing channels that contribute to enhanced invasion and metastasis of granule precursor-derived human medulloblastoma. Aberrant intracellular Ca signalling contributes to the formation and progression of a range of distinct pathologies including cancers. Rises in intracellular Ca concentration occur in response to Ca influx through plasma membrane channels and Ca release from intracellular Ca stores, which can be mobilized in response to activation of cell surface receptors. Ovarian cancer G protein coupled receptor 1 (OGR1, aka GPR68) is a proton-sensing G -coupled receptor that is most highly expressed in cerebellum. Medulloblastoma (MB) is the most common paediatric brain tumour that arises from cerebellar precursor cells. We found that nine distinct human MB samples all expressed OGR1. In both normal granule cells and the transformed human cerebellar granule cell line DAOY, OGR1 promoted expression of the proton-potentiated member of the canonical transient receptor potential (TRPC) channel family, TRPC4. Consistent with a role for TRPC4 in MB, we found that all MB samples also expressed TRPC4. In DAOY cells, activation of TRPC4-containing channels resulted in large Ca influx and enhanced migration, while in normal cerebellar granule (precursor) cells and MB cells not derived from granule precursors, only small levels of Ca influx and no enhanced migration were observed. Our results suggest that OGR1-dependent increases in TRPC4 expression may favour formation of highly Ca -permeable TRPC4-containing channels that promote transformed granule cell migration. Increased motility of cancer cells is a prerequisite for cancer invasion and metastasis, and our findings may point towards a key role for TRPC4 in progression of certain types of MB.

Wei-Chun Wei, Wan-Chen Huang, Yu-Ping Lin, Esther B E Becker, Olaf Ansorge, Veit Flockerzi, Daniele Conti, Giovanna Cenacchi, Maike D Glitsch