Biology subjects

Lehmann, M.

Publications and source records attributed to Lehmann, M..

3 recordsLinked to original sources

bioRxiv2018

The splicing regulator Prp31 prevents retinal degeneration in Drosophila by regulating Rhodopsin levels

Retinitis pigmentosa (RP) is a clinically heterogeneous disease affecting 1.6 million people worldwide. The second-largest group of genes causing autosomal dominant RP in human encodes regulators of the splicing machinery, but the molecular consequences that link defects in splicing factor genes to the aetiology of the disease remain to be elucidated. Mutations in PRPF31, one of the splicing factors, are linked to RP11. To get insight into the mechanisms by which mutations in this gene lead to retinal degeneration, we induced mutations in the Drosophila orthologue Prp31. Flies heterozygous mutant for Prp31 are viable and develop normal eyes and retina. However, photoreceptors degenerate under light stress, thus resembling the human disease phenotype. Prp31 mutant flies show a high degree of phenotypic variability, similar as reported for human RP11 patients. Degeneration is associated with increased accumulation of rhodopsin 1, both in the rhabdomere and in the cell body. In fact, reducing rhodopsin levels by raising animals in a carotenoid-free medium not only suppressed rhodopsin accumulation, but also retinal degeneration. In addition, our results underscore the relevance of eye color mutations on phenotypic traits, in particular whilst studying a complex process such as retinal degeneration.\n\nArticle SummaryRetinitis pigmentosa (RP) is a human disease affecting 1.6 million people worldwide. So far >50 genes have been identified that are causally related to RP. Mutations in the splicing factor PRPF31 are linked to RP11. We induced mutations in the Drosophila orthologue Prp31 and show that flies heterozygous for Prp31 undergo light-dependent retinal degeneration. Degeneration is associated with increased accumulation of the light-sensitive molecule, rhodopsin 1. In fact, reducing rhodopsin levels by dietary intervention suppressed retinal degeneration. We believe that this model will help to better understand the aetiology of the human disease.

genetics↗

bioRxiv2018

The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension

Mutations that destabilize superoxide dismutase 1 (SOD1) are a cause of amyotrophic lateral sclerosis (ALS). SOD1, which is located in the reducing cytosol, contains an oxidized disulfide bond required for stability. We show that the bond is an Achilles heel of the protein because it is sensitive to the oxygen tension. Culture of ALS patient-derived fibroblasts, astrocytes and induced pluripotent stem cell-derived mixed motor neuron and astrocyte cultures (MNACs) under lowered oxygen tensions caused reductive bond cleavage and misfolding. The effects were greatest in cells expressing mutant SOD1s, but also occurred in wild type SOD1 in cultures derived from patients carrying ALS-linked mutations in C9orf72, FUS and TBK1, as well as from controls. MNACs showed a greater response than the other cell types, including enhanced SOD1 aggregation, in line with the vulnerability of the motor system. Our results show that oxygen tension is a principal determinant of SOD1 stability and shed light on how risk factors for ALS, such as aging and other conditions causing reduced vascular perfusion, could lead to disease initiation and progression.\n\nSubject categories Neuroscience; Molecular Biology of Disease

neuroscience↗

bioRxiv2017

Mutations in the Drosophila splicing regulator Prp31 as a model for Retinitis pigmentosa 11

Retinitis pigmentosa is a clinically heterogeneous disease affecting 1.6 million people worldwide. A growing number of identified disease-causing genes are associated with the spliceosome, but the molecular consequences that link defects in splicing factor genes to the aetiology of the disease remain to be elucidated. In this paper, we present a Drosophila model for Retinitis pigmentosa 11, a human disease caused by mutations in the splicing factor PRPF31. Here, we induced mutations in the Drosophila orthologue Prp31. Mutant flies are viable and show a normal eye phenotype when kept under regular light conditions. However, when exposed to constant light, photoreceptors of mutant flies degenerate, thus resembling the human disease phenotype. Degeneration could be shown to be associated with increased oxidative stress. This increase was in agreement with severe dysregulation of genes involved in oxidation/reduction processes, as revealed by high throughput transcriptome sequencing. In fact, light induced photoreceptor cell degeneration could be attenuated by experimentally reducing oxidative stress. A comparable decrease in retinal degeneration was achieved by raising mutant larvae on a vitamin A-depleted medium, thereby reducing rhodopsin levels. Finally, transcriptome data further uncovered an overall retention of introns in mRNAs. Among those, mRNAs of genes involved in synapse assembly, growth and stability were most prominent. These results point to a multifactorial genesis of light induced degeneration in retinae of Prp31 mutant flies, including transcriptional and splicing dysregulation, oxidative stress and defects in vitamin A metabolism.

genetics↗