Biology subjects

Hayes, L.

Publications and source records attributed to Hayes, L..

3 recordsLinked to original sources

bioRxiv2020

An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients

Neurodegenerative diseases present a challenge for systems biology, due to the lack of reliable animal models and the difficulties in obtaining samples from patients at early stages of disease, when interventions might be most effective. Studying induced pluripotent stem cell (iPSC)-derived neurons could overcome these challenges and dramatically accelerate and broaden therapeutic strategies. Here we undertook a network-based multi-omic characterization of iPSC-derived motor neurons from ALS patients carrying genetically dominant hexanucleotide expansions in C9orf72 to gain a deeper understanding of the relationship between DNA, RNA, epigenetics and protein in the same pool of tissue. ALS motor neurons showed the expected C9orf72-related alterations to specific nucleoporins and production of dipeptide repeats. RNA-seq, ATAC-seq and data-independent acquisition mass-spectrometry (DIA-MS) proteomics were then performed on the same motor neuron cultures. Using integrative computational methods that combined all of the omics, we discovered a number of novel dysregulated pathways including biological adhesion and extracellular matrix organization and disruption in other expected pathways such as RNA splicing and nuclear transport. We tested the relevance of these pathways in vivo in a C9orf72 Drosophila model, analyzing the data to determine which pathways were causing disease phenotypes and which were compensatory. We also confirmed that some pathways are altered in late-stage neurodegeneration by analyzing human postmortem C9 cervical spine data. To validate that these key pathways were integral to the C9 signature, we prepared a separate set of C9orf72 and control motor neuron cultures using a different differentiation protocol and applied the same methods. As expected, there were major overall differences between the differentiation protocols, especially at the level of in individual omics data. However, a number of the core dysregulated pathways remained significant using the integrated multiomic analysis. This new method of analyzing patient specific neural cultures allows the generation of disease-related hypotheses with a small number of patient lines which can be tested in larger cohorts of patients.

neuroscience↗

bioRxiv2020

Only two out of five articles by New Zealand researchers are free-to-access: a multiple API study of access, its impact on open citation advantage, cost of Article Processing Charges (APC), and the potential to increase the proportion of open access

We studied journal articles published by researchers at all eight of New Zealand universities in 2017 to determine how many were freely accessible on the web. We wrote software code to harvest data from multiple sources, code that we now share to enable others to reproduce our work on their own sample set. In May 2019, we ran our code to determine which of the 2017 articles were open at that time and by what method; where those articles would have incurred an Article Processing Charge (APC) we calculated the cost if those charges had been paid. Where articles were not freely available we determined whether the policies of publishers in each case would have allowed deposit in a non-commercial repository (Green open access). We also examined citation rates for different types of access. We found that, of our 2017 sample set, about two out of every five articles were freely accessible without payment or subscription (41%). Where research was explicitly said to be funded by New Zealands major research funding agencies, the proportion was slightly higher at 45%. Where open articles would have incurred an APC we estimated an average cost per article of USD1,682 (for publications where all articles require an APC, that is, Gold open access) and USD2,558 (where APC payment is optional, Hybrid open access) at a total estimated cost of USD1.45m. Of the paid options, Gold is by far more common for New Zealand researchers (82% Gold, 18% Hybrid). In terms of citations, our analysis aligned with previous studies that suggest a correlation between publications being freely accessible and, on balance, slightly higher rates of citation. This is not seen across all types of open access, however, with Diamond OA achieving the lowest rates. Where articles were not freely accessible we found that a very large majority of them (88% or 3089 publications) could have been legally deposited in an institutional repository. Similarly, only in a very small number of cases had a version deposited in the repository of a New Zealand university made the difference between the publication being freely accessible or not (125 publications). Given that most New Zealand researchers support research being open, there is clearly a large gap between belief and practice in New Zealands research ecosystem.

scientific communication and education↗

bioRxiv2020

G4C2 repeat RNA mediates the disassembly of the nuclear pore complex in C9orf72 ALS/FTD

Nucleocytoplasmic transport, controlled by the nuclear pore complex, has recently emerged as a pathomechanism underlying neurodegenerative diseases including C9orf72 ALS/FTD. However, little is known about the underlying molecular events and the underlying biology in human neurons. Using super resolution structured illumination microscopy of twenty three nucleoporins in nuclei from C9orf72 iPSC derived neurons and postmortem human tissue we identify a unique subset of eight nucleoporins lost from human neuronal nuclei. POM121, an integral transmembrane nucleoporin, appears to coordinate the composition of the nucleoporins within human neuronal nuclei ultimately impacting nucleocytoplasmic transport, and subsequent cellular toxicity in C9orf72 iPSNs. These data suggest that POM121 is a critical nucleoporin in the maintenance of the nuclear localization of specific nucleoporins in human neurons. Moreover, loss of nuclear POM121, as a result of expanded C9orf72 ALS/FTD repeat RNA, initiates a pathological cascade affecting nucleoporin composition within neuronal nuclei, nuclear pore complex function, and overall downstream neuronal survival.

neuroscience↗