The developmental basis of dopaminergic neuron diversity

描述(申请人提供)：帕金森氏病(PD)患者严重的运动障碍主要是由中脑多巴胺神经元(MDA)的大量丧失引起的。仔细的形态计量学研究揭示了某些丙二醛群体的选择性易感性。因此，位于黑质致密部腹侧层(SNPC；A9)的丙二醛神经元比位于SNPC背侧层或腹侧被盖区(A10)的丙二醛神经元更脆弱。这种不同的易感性突出了丙二醛种群的多样性。我们假设，在发育中的中脑中，有多个不同的丙二醛前体池，每个池都产生不同的丙二醛亚型。我们将尝试确定帕金森病中最敏感类型的多巴胺神经元的祖细胞池。因此，我们将追踪一个提出的丙二醛前体细胞池，并确定其后代是否存在于多巴胺能区最脆弱的区域，即SNPC的腹侧层。接下来，我们将为这个DA亚型绘制地形图。总而言之，这些实验将第一次让我们一窥丙二醛多样性是如何产生的。阐明这种多样性的发育基础对于理解丙二醛的不同易感性以及产生准确的ES或IPSC干细胞来源的PD模型和治疗方法至关重要。 公共卫生相关性：在帕金森氏症中，精选的多巴胺神经元亚群容易退化。我们的目的是证明这是因为多巴胺神经元与它们出生时的本质不同。

DESCRIPTION (provided by applicant): The drastic motor deficit in Parkinson's disease (PD) patients is largely caused by a substantial loss of midbrain dopamine neurons (mDA). Careful morphometric studies have revealed a selective susceptibility of certain mDA populations. Thus, mDA neurons found in the ventral tier of the substantia nigra pars compacta (SNpc; A9) are more vulnerable, compared to mDA located in the dorsal tier of the SNpc, or in the Ventral Tegmental Area (A10). This differential susceptibility highlights the diversity of mDA populations. We hypothesize that in the developing midbrain, there are multiple distinct mDA progenitor pools, each of which gives rise to distinct mDA subtypes. We will attempt to determine the progenitor pool for the most susceptible type of dopamine neuron in PD. Accordingly, we will lineage trace one proposed mDA progenitor pool and determine whether its descendents populate the most vulnerable regions of the dopaminergic field i.e. the ventral tier of the SNpc. Next we will develop topographic maps for this DA subtype. Together, these experiments will provide a first glimpse into how mDA diversity is generated. Elucidating the developmental basis for this diversity will be critical for understanding differential susceptibility of mDA, as well as generating accurate ES or iPSC stem cell derived models and therapies for PD. PUBLIC HEALTH RELEVANCE: In Parkinson's disease, a select subset of dopamine neurons is prone to degeneration. We aim to demonstrate that this is because dopamine neurons are inherently different from the time of their birth.