NHE6-mediated endosomal defects in neurodegenerative disorders

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PROJECT SUMMARY/ABSTRACT There are critical gaps in our understanding of the endosomal pathway and its functional impact on the patho- genesis of neurodegenerative disorders such as Alzheimer’s disease (AD) and AD-related dementia (ADRD). The overarching goal of this study is to build an independent research program dedicated to elucidating the cellular mechanisms of neurodegeneration and discovering novel therapeutic targets. The objective of this pro- posal is to reveal the endosomal dysfunction that causes neurodegeneration in Christianson syndrome, as well as to establish mechanistic links to related neurodegenerative disorders such as AD/ADRD. Loss-of-function mutations in Na+/H+Exchanger 6 (NHE6) cause an endosomal neurological disorder called Christianson syn- drome (CS), which presents tau-associated neurodegenerative pathologies. We have recently published a new study describing a novel rat model of CS, which better represents neurodegenerative features than the current mouse model. The central hypothesis is that NHE6 deletion impairs late endosomal function, which may contrib- ute to AD/ADRD-related pathologies. The rationale for this study is to establish a better understanding of defec- tive endosomal pathways which may act as a pathogenic hub in CS and AD/ADRD. Together with my recently published work and preliminary data, mounting evidence emphasizes the function of NHE6 in AD/ADRD. Ex- panding our knowledge of the NHE6-mediated endosomal pathway will accelerate the identification of novel therapeutic targets for CS and AD/ADRD. This proposal will take multidisciplinary approaches including ad- vanced imaging methods. During the mentored K99 phase, mechanisms whereby the loss of NHE6 disrupt ax- onal transport (Aim1) and late endosomal maturation (Aim2) will be defined. Aim1 and Aim2 will be performed under the guidance of Dr. Eric Morrow, who is a leader in the field of endolysomal cell biology and rare neuro- genetic disorders including CS. My advisory team will bring unique and complementary skills and knowledge, which will further enhance my training. During the K99 phase, I will boost my expertise in advanced super- resolution microscope (SRM) imaging and broaden my knowledge in endolysomal cell biology and neurodegen- erative disorders, especially AD/ADRD. I will utilize these acquired skills and knowledge to perform the R00 aim (Aim3), which will determine the impact of NHE6 deletion on AD/ADRD pathology in a transgenic AD rat model. This proposal ise methodologically and conceptually innovative. It will utilize SRM and novel rat models, as rats are more genetically and physiologically closer to humans than mice. Also, it will refine our current view of NHE6 function and reveal endosomal dysfunction in neurodegenerative disorders. Overall, this proposal will allow me to acquire rigorous scientific training in both neuronal cell biology and neurodegeneration through the strong mentorship and research program. This award will enable me to launch an independent research program ded- icated to elucidating cellular mechanisms of neurodegenerative diseases and other aging-related disorders.