Analysis of the substrate network and neurodevelopmental functions of the intellectual disability enzyme, zDHHC9

认知和精神疾病的新治疗方法的发展需要对导致这些疾病的潜在生物扰动有详细的了解。虽然类似的神经系统疾病可能由大量不同的基因突变引起，但这些疾病的发展很可能是由于共同细胞通路的破坏。ZDHHC9基因编码一种将脂肪附着在细胞蛋白质上的酶，这种基因的突变会导致智力残疾、癫痫、语言和注意力问题。此外，该基因的突变还会扰乱胼胝体，胼胝体是一个大脑区域，负责调节大脑两侧之间的交流，在一系列神经发育障碍中被破坏。这项资助的目的是使用缺乏Zdhhc9的小鼠模型来研究可能导致Zdhhc9突变的人类神经功能缺陷的分子和细胞变化。具体来说，我们将确定Zdhhc9的缺失如何导致胼胝体的破坏，并确定与该脑区域缺陷相关的该酶的关键底物。此外，我们将通过研究这些小鼠的运动和注意力行为来评估Zdhhc9突变小鼠是否表现出与Zdhhc9突变小鼠相同的全部行为变化。除了提供关于ZDHHC9突变如何破坏大脑功能的新见解之外，这一新知识还可以提高我们对普通人群中更常见的神经系统疾病的理解。

Development of new treatments and cures for cognitive and psychiatric disorders requires a detailed understanding of the underlying biological perturbations that cause these conditions. Although similar neurological conditions can be caused by a large array of different gene mutations, it is likely that these disorders develop due to disruption of common cellular pathways. Mutations in the ZDHHC9 gene, which encodes an enzyme that attaches fats onto cellular proteins, causes intellectual disability, seizures, and speech and attention problems. Furthermore, mutations in this gene also perturb the corpus callosum, a brain region that mediates communication between the two sides of the brain, and which is disrupted in a range of neurodevelopmental disorders. The aim of this grant is to use a mouse model lacking Zdhhc9 to investigate the molecular and cellular changes that might lead to the neurological deficits seen in humans with ZDHHC9 mutations. Specifically, we will determine how loss of Zdhhc9 leads to disruption of the corpus callosum and identify key substrates of this enzyme that are linked to deficits in this brain region. Furthermore, we will assess if Zdhhc9 mutant mice exhibit the full spectrum of behavioural changes seen in humans with ZDHHC9 mutations by investigating oromotor and attention behaviours in these mice. In addition to providing new insight into how ZDHHC9 mutations disrupt brain function, this new knowledge may also improve our understanding of more common neurological disorders in the general population.