Single-cell transcriptional landscape of peripheral immunity and biomarkers for human sporadic amyotrophic lateral sclerosis patients

Sporadic amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease with unknown causes and few treatment options. Here we report the first multi-dimensional single-cell landscape of the peripheral blood mononuclear cell samples from seven ALS patients representing three distinct disease stages: Early, Mid and Late. Our multipronged analyses revealed the over-activation of immune cells especially in the Mid and Late ALS stages, which is characterized by the increased cytotoxic CD8+ effector cells, expanded TCR clonotypes, upregulated oxidative phosphorylation and ribosomal genes across many cell types. More importantly, the current study discovered novel genes strongly correlated with ALS conditions, such as FOXO1 and TGFBR2 responsible for the aberrant T cell activation, and XBP1 and SPIB accountable for excessive oxidative stress. We further identified 60 genes that distinguished ALS patients from healthy donors with an unprecedented accuracy of 93% against an independent cohort of 792 specimens. Our findings provide new molecular and cellular insights into the mechanisms of ALS onset and progression, and offer novel strategies for accurate diagnosis and potential therapeutic development. ### Competing Interest Statement Q.W. is an employee of Harcam Biomedicines who is bound by confidentiality agreements that prevents her from disclosing the competing interests in this work. All remaining authors declare no competing interest. ### Funding Statement This work was partially supported by Major Special Program Grant of Shanghai Municipality (Award Number 2017SHZDZX01), National Key Research and Development Program of China (Award Number 2021YFF1200400) and Shanghai Municipal Science and Technology Major Project (Award Number 2018SHZDZX01). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Ethics Committee of the Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine (Approval #2020-060-02). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors