Molecular correlates of sub-regional thalamic degeneration in multiple sclerosis

摘要 多发性硬化（MS）是一种免疫介导的中枢神经系统疾病 包括脱髓鞘和白色物质和灰质的退化。深灰质 结构，如丘脑，由于它们的早期功能， 体积损失丘脑不仅仅是一个“中继站”;组织传入和传出 信息处理，它与多个区域的连接性暗示它与疲劳和运动有关， 认知和感觉障碍。丘脑萎缩是MS患者残疾的预测因素 和认知障碍，以及临床- 虽然丘脑萎缩是建立在MS，确切的机制， 潜在的丘脑变性没有很好的特征。我们组建了一支强大的团队， 研究人员与跨学科和互补的专业知识，以确定分子 最近的数据支持这一假设，即脱髓鞘 丘脑外，影响功能和解剖连接，可能会驱动选择性 丘脑内的神经退化初步结果已经确定了丘脑的三个区域： 膝状体核（LGN）、枕（PV）核和中央内侧（CM）核作为a）具有 优先容量损失，和B）与患者中更大的神经功能障碍显著相关 因此，我们假设，某些丘脑下丘脑的优先体积损失， 区域可能是由于其神经元/神经胶质群体的选择性脆弱性。使用死后核磁共振成像， 我们确定了尸检MS脑的队列， 丘脑脱髓鞘此外，我们还包括一个最近发现的新的MS组 无任何白质病变，但丘脑萎缩相当的患者（称为骨髓皮质MS）。 因此，这项探索性建议的主要目标是生成、鉴定和验证一种分子生物学方法。 使用单细胞RNA测序（sc-RNA seq）的MS中丘脑体积损失的代表性模式。 拟议研究将使用充分表征的样本进行目标1a）sc-RNA测序;目标1b）空间 目的1c）验证新的细胞簇，以研究分子生物学。 这些研究将揭示遗传特征， 与MS患者中脆弱并导致体积损失的丘脑区域相关。 目前研究的成功完成将为今后的研究迈出重要的一步 监测并最终预防MS患者的丘脑萎缩和神经变性。

ABSTRACT Multiple sclerosis (MS) is an immune-mediated disease of the human central nervous system (CNS) that involves demyelination and degeneration of both white matter and gray matter. Deep grey-matter structures such as the thalamus have received significant attention in MS research due to their early volume loss. The thalamus is far more than just a “relay station”; organizing afferent and efferent information processing, its connectivity to multiple regions implicates it in fatigue as well as motor, cognitive, and sensory impairments in individuals with MS. Thalamic atrophy is a predictor of disability and cognitive impairment in all disease courses of MS, as well as a predictor for conversion of clinically- isolated syndrome into MS. While thalamic atrophy is established in MS, the exact mechanisms underlying thalamic degeneration are not well-characterized. We have assembled a strong team of investigators with interdisciplinary and complementary expertise in order to identify the molecular correlates of the thalamic degeneration in MS. Recent data support the hypothesis that demyelination outside the thalamus, affecting the functional and anatomic connections, may drive selective neurodegeneration within the thalamus. Preliminary results have identified three thalamic regions: lateral geniculate nucleus (LGN), pulvinar (PV) nucleus, and centro-medial (CM) nucleus as a) having preferential volume loss, and b) significantly correlating with greater neurological disability in patients with progressive MS. We therefore hypothesize that preferential volume loss of certain thalamic sub- regions may be due selective vulnerability of their neuronal/glial populations. Using postmortem MRI, we identified cohorts of postmortem MS brains with mild or severe volume loss and minimal demyelination in the thalamus. In addition, we also include a recently-identified novel group of MS patients (termed myelocortical MS) without any white-matter lesions, but comparable thalamic atrophy. The main goal of this exploratory proposal is therefore to generate, identify, and validate a molecular pattern representative of thalamic volume loss in MS using single-cell RNA sequencing (sc-RNA seq). The proposed study will use well-characterized samples for Aim 1a) sc-RNA seq; Aim 1b) spatial transcriptomic assays; and Aim 1c) validation of novel cell clusters to investigate the molecular alterations underlying thalamic atrophy in MS. These studies will reveal the genetic signatures associated with thalamic regions that are vulnerable and contribute to volume loss in MS patients. Successful completion of the current study will provide a significant step forward towards future research in monitoring and eventually preventing thalamic atrophy and neurodegeneration in MS patients.