Spatial enrichment and genomic analyses reveal the link of NOMO1 with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease with uncertain genetic predisposition in most sporadic cases. The spatial architecture of cell types and gene expression are the basis of cell-cell interactions, biological function and disease pathology, but are not well investigated in the human motor cortex, a key ALS-relevant brain region. Recent studies indicated single nucleus transcriptomic features of motor neuron vulnerability in ALS motor cortex. However, the brain regional vulnerability of ALS-associated genes and the genetic link between region-specific genes and ALS risk remain largely unclear. Here, we developed an entropy-weighted differential gene expression matrix-based tool (SpatialE) to identify the spatial enrichment of gene sets in spatial transcriptomics. We benchmarked SpatialE against another enrichment tool (multimodal intersection analysis) using spatial transcriptomics data from both human and mouse brain tissues. To investigate regional vulnerability, we analysed three human motor cortex and two dorsolateral prefrontal cortex tissues for spatial enrichment of ALS-associated genes. We also used Cell2location to estimate the abundance of cell types in ALS-related cortex layers. To dissect the link of regionally expressed genes and ALS risk, we performed burden analyses of rare loss-of-function variants detected by whole-genome sequencing in ALS patients and controls, then analysed differential gene expression in the TargetALS RNA-sequencing dataset. SpatialE showed more accurate and specific spatial enrichment of regional cell type markers than multimodal intersection analysis in both mouse brain and human dorsolateral prefrontal cortex. Spatial transcriptomic analyses of human motor cortex showed heterogeneous cell types and spatial gene expression profiles. We found that 260 manually curated ALS-associated genes are significantly enriched in layer 5 of the motor cortex, with abundant expression of upper motor neurons and layer 5 excitatory neurons. Burden analyses of rare loss-of-function variants in Layer 5-associated genes nominated NOMO1 as a novel ALS-associated gene in a combined sample set of 6814 ALS patients and 3324 controls (P = 0.029). Gene expression analyses in CNS tissues revealed downregulation of NOMO1 in ALS, which is consistent with a loss-of-function disease mechanism. In conclusion, our integrated spatial transcriptomics and genomic analyses identified regional brain vulnerability in ALS and the association of a layer 5 gene (NOMO1) with ALS risk.

Exosomes: The endogenous nanomaterials packed with potential for diagnosis and treatment of neurologic disorders.

Neurologic disorders (NDs) are serious diseases that threaten public health. However, due to the complex pathogenesis and significant individual differences in traditional treatments, specific treatment methods for NDs are still lacking. Exosomes, the smallest extracellular vesicles secreted by eukaryotic cells, are receiving increasing attention in the field of NDs. They contain misfolded proteins related to various NDs, including amyloid-beta, Tau proteins, and α-synuclein, indicating their promising roles in the diagnosis and treatment of NDs. In this review, an overview of the biogenesis, composition, and biological functions of exosomes is provided. Moreover, we summarize their potential roles in the pathogenesis of three prevalent NDs (including Alzheimer's disease, Ischemic stroke, and Parkinson's disease). On this basis, the diagnostic potential and therapeutic value of exosomes carrying various bioactive molecules are discussed in detail. Also, the concerns and perspectives of exosome-based diagnosis and therapy are discussed.