Abstract：
Age is the primary risk factor for Parkinson\'s disease (PD), but how aging changes the expression and regulatory landscape of the brain remains unclear. Here we present a single-nuclei multiomic study profiling shared gene expression and chromatin accessibility of young, aged and PD postmortem midbrain samples. Combined multiomic analysis along a pseudopathogenesis trajectory reveals that all glial cell types are affected by age, but microglia and oligodendrocytes are further altered in PD. We present evidence for a disease-associated oligodendrocyte subtype and identify genes lost over the aging and disease process, including CARNS1, that may predispose healthy cells to develop a disease-associated phenotype. Surprisingly, we found that chromatin accessibility changed little over aging or PD within the same cell types. Peak-gene association patterns, however, are substantially altered during aging and PD, identifying cell-type-specific chromosomal loci that contain PD-associated single-nucleotide polymorphisms. Our study suggests a previously undescribed role for oligodendrocytes in aging and PD.
摘要：
年龄是帕金森病（PD）的主要危险因素，但是衰老如何改变大脑的表达和调节景观仍不清楚。在这里，我们提出了一个单核多组研究分析共享的基因表达和染色质可及性的年轻，老年人和PD死后中脑样本。沿着假病发生轨迹的联合多体分析显示，所有神经胶质细胞类型都受年龄的影响，但是小胶质细胞和少突胶质细胞在PD中进一步改变。我们提供了疾病相关的少突胶质细胞亚型的证据，并确定了在衰老和疾病过程中丢失的基因。包括CARNS1，这可能会使健康细胞产生与疾病相关的表型。令人惊讶的是,我们发现，在相同细胞类型中，染色质可及性随衰老或PD变化不大。峰值基因关联模式，然而,在老化和PD期间发生了实质性变化，鉴定含有PD相关单核苷酸多态性的细胞类型特异性染色体基因座。我们的研究表明，少突胶质细胞在衰老和PD中具有以前未描述的作用。
