@article{22544d69b6aa4df39e78a0dc7010efac,
title = "Synaptic proteomics reveal distinct molecular signatures of cognitive change and C9ORF72 repeat expansion in the human ALS cortex",
abstract = "Increasing evidence suggests synaptic dysfunction is a central and possibly triggering factor in Amyotrophic Lateral Sclerosis (ALS). Despite this, we still know very little about the molecular profile of an ALS synapse. To address this gap, we designed a synaptic proteomics experiment to perform an unbiased assessment of the synaptic proteome in the ALS brain. We isolated synaptoneurosomes from fresh-frozen post-mortem human cortex (11 controls and 18 ALS) and stratified the ALS group based on cognitive profile (Edinburgh Cognitive and Behavioural ALS Screen (ECAS score)) and presence of a C9ORF72 hexanucleotide repeat expansion (C9ORF72-RE). This allowed us to assess regional differences and the impact of phenotype and genotype on the synaptic proteome, using Tandem Mass Tagging-based proteomics. We identified over 6000 proteins in our synaptoneurosomes and using robust bioinformatics analysis we validated the strong enrichment of synapses. We found more than 30 ALS-associated proteins in synaptoneurosomes, including TDP-43, FUS, SOD1 and C9ORF72. We identified almost 500 proteins with altered expression levels in ALS, with region-specific changes highlighting proteins and pathways with intriguing links to neurophysiology and pathology. Stratifying the ALS cohort by cognitive status revealed almost 150 specific alterations in cognitively impaired ALS synaptic preparations. Stratifying by C9ORF72-RE status revealed 330 protein alterations in the C9ORF72-RE +ve group, with KEGG pathway analysis highlighting strong enrichment for postsynaptic dysfunction, related to glutamatergic receptor signalling. We have validated some of these changes by western blot and at a single synapse level using array tomography imaging. In summary, we have generated the first unbiased map of the human ALS synaptic proteome, revealing novel insight into this key compartment in ALS pathophysiology and highlighting the influence of cognitive decline and C9ORF72-RE on synaptic composition.",
keywords = "ALS, Synapse, Proteomics, FTD, C9ORF72, Human brain",
author = "Zsofia Laszlo and Nicole Hindley and {Sanchez Avila}, Anna and Rachel Kline and Sam Eaton and Lamont, {Douglas J} and Colin Smith and Tara Spires-Jones and Thomas Wishart and Christopher Henstridge",
note = "Funding Information: We gratefully acknowledge the generous donors who have made this work possible. We wish to acknowledge the CARE-MND Register, hosted by the Euan Macdonald Centre (EMC) for MND Research and funded by MND Scotland. We are extremely thankful for the hard work of the Scottish MND Clinical Specialist Team for obtaining consent for tissue donation, led by Judith Newton. We thank Dominic Kurian from the Roslin Institute Proteomic and Metabolomic Facility for advice. Funding Information: We gratefully acknowledge the generous donors who have made this work possible. We wish to acknowledge the CARE-MND Register, hosted by the Euan Macdonald Centre (EMC) for MND Research and funded by MND Scotland. We are extremely thankful for the hard work of the Scottish MND Clinical Specialist Team for obtaining consent for tissue donation, led by Judith Newton. We thank Dominic Kurian from the Roslin Institute Proteomic and Metabolomic Facility for advice. Funding Information: CMH acknowledges funding support from MND Scotland, TENOVUS Scotland and Alzheimer{\textquoteright}s Research UK (ARUK-EG2019B-003). This work was funded by a Lady Edith Wolfson Junior Non-Clinical Fellowship to Z.I.L from the MND Association (Laszlo/Oct21/977-799). ASA is funded by a Euan Macdonald Centre for Motor Neuron Disease Research PhD studentship. TSJ receives funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 681181) and the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK. RAK was funded by the Euan Macdonald Centre for Motor Neuron Disease Research PhD studentship, and the University of Edinburgh's Principal's Career Development and Global Research scholarships. TMW and SLE are supported by funding from the Biotechnology and Biological Sciences Research Council (BBSRC) Institute Strategic Grant No. (BBS/E/D/10002071). Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = oct,
day = "29",
doi = "10.1186/s40478-022-01455-z",
language = "English",
volume = "10",
pages = "1--20",
journal = "Acta Neuropathologica Communications",
issn = "2051-5960",
publisher = "BMC",
number = "156",
}