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Enhanced deoxysphingobase production in HSN1 results in sensory nerve toxicity through deficits in both cell autonomous and axoglial signalling, ameliorated by serine treatment

ABSTRACT: Hereditary sensory neuropathy type 1 (HSN1) is caused by mutations in either the SPTLC1 or SPTLC2 sub-units of the enzyme Serine Palmitoyl Transferase resulting in the production of Deoxyshingobases (DSBs). Exogenous DSBs are toxic when acutely applied to neurons however it’s unknown whether endogenous DSBs are neurotoxic and the mechanism of such toxicity. Using induced pleuripotent stem cells (iPSC) from HSN1 patients we found increased DSB production from both hepatocytes and sensory neurons. Gene expression profiling in HSN1 iPSCd-sensory neurons showed dysregulation in axon outgrowth and lipid signalling pathways. We noted reduced lipid raft formation, impaired growth factor signalling and reduced neurite outgrowth in these neurons. Gangliosides which are essential for membrane dynamics and lipid raft formation and were globally reduced due to feedback inhibition of DSBs on the enzyme… In co-cultures between HSN1 iPSCd-sensory neurons and rat Schwann the nodal complex and myelin were disrupted. HSN1 SPTLC mutations therefor impair cell autonomous and inter-cellular signalling due to altered lipid metabolism, changes which could largely be prevented by treatment with Serine (which reduces DSB production) supporting Serine as a rational therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144208 | GEO | 2020/03/25

REPOSITORIES: GEO

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Project description:DNA double-strand breaks (DSBs) initiate meiotic recombination. Past DSB-mapping studies have used rad50S or sae2? mutants, which are defective in break processing, to accumulate DSBs, and report large (= 50 kb) “DSB-hot” regions that are separated by “DSB-cold” domains of similar size. Substantial recombination occurs in some DSB-cold regions, suggesting that DSB patterns are not normal in rad50S or sae2? mutants. We therefore developed novel methods that detect DSBs using ssDNA enrichment and microarray hybridization, and that use background-based normalization to allow cross-comparison between array datasets, to map genome-wide the DSBs that accumulate in processing-capable, repair-defective dmc1î and dmc1î rad51î mutants. DSBs were observed at known hotspots, but also in most previously-identified “DSB-cold” regions, including near centromeres and telomeres. While about 40% of the genome is DSB-cold in rad50S mutants, analysis of meiotic ssDNA from dmc1? shows that most of these regions have significant DSB activity. Thus, DSBs are distributed much more uniformly than was previously believed. Southern-blot assays of DSBs in selected regions in dmc1?, rad50S and wild-type cells confirm these findings. Comparisons of DSB signals in dmc1, dmc1 rad51, and dmc1 spo11 mutant strains identify Dmc1 as the primary strand transfer activity genome-wide, and Spo11-induced lesions as initiating all meiotic recombination. Keywords: DSB mapping, ChIP-chip, single strand DNA , BND cellulose We use two different strategies to map the genome-wide distribution of meiotic DSBs in the yeast Saccharomyces cerevisiae. The first is a chromatin immunoprecipitation (ChIP) based approach that targets the Spo11p protein, which remains covalently attached to DSB ends in the rad50S mutant background. The second approach involves BND cellulose enrichment of the single strand DNA (ssDNA) recombination intermediate formed by end-resection at DSB sites following Spo11p removal. We use dmc1 and dmc1 rad51 mutants that accumulates meiotic single strand DNA intermediates

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Enhanced deoxysphingobase production in HSN1 results in sensory nerve toxicity through deficits in both cell autonomous and axoglial signalling, ameliorated by serine treatment

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