Single-cell sequencing identifies a novel T-lymphocyte cluster expressing stemness genes in amyotrophic lateral sclerosis patients
Ma, A. Z.; Kirk, B. D.; Yan, D.; Wang, Q.; Han, Y.; Ying, W.
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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.
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