Investigating the Role of GDE2 in Neuronal Mitotic Inhibition and Nuclear Pore Complex Defects

Project Summary / Abstract Alzheimer's disease (AD) and related diseases (ADRDs) are the leading cause of dementia, affecting millions of people each year. Despite being such a prevalent public health concern, knowledge of the etiology of neurodegeneration in these diseases is limited and has stymied the development of effective treatments.

Aberrant neuronal cell-cycle reentry (CCR) and nuclear pore complex (NPC)/nucleocytoplasmic transport defects have been separately identified as causal phenomena for neurodegeneration in AD and ADRDs. However, the mechanisms leading to these phenomena and the relationship between them remains unknown.

We have identified a pathway involving Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) that prevents CCR and NPC/nucleocytoplasmic transport defects in the adult mammalian brain and is disrupted in human postmortem AD and ALS brain tissue. GDE2 is one of three six-transmembrane enzymes that act at the

cell surface to cleave the GPI-anchor that tethers some proteins to the membrane. During embryogenesis, GDE2 inhibits progenitor cell proliferation to promote neuronal differentiation. Preliminary studies show that loss of GDE2 in the adult brain leads to CCR and NPC abnormalities that precede overt neurodegeneration. Because

NPC defects are coincident with CCR in neurons lacking GDE2, and the NPC normally breaks down during mitosis, we hypothesize that GDE2 is important for maintaining neurons in a postmitotic state throughout life and that aberrant CCR elicited by GDE2 loss leads to NPC breakdown and neurodegeneration. Importantly, GDE2

localization and function is disrupted in AD and ADRDs, raising the possibility that dysfunction of the GDE2 pathway could contribute to the pathogenesis of these diseases. This proposal will test our central hypothesis in three aims. Aim 1 will define the physiological requirement for GDE2 in maintaining neuronal quiescence and

NPC integrity in aging mice while Aim 2 will define the relationship between CCR and NPC breakdown and identify the mechanisms leading to CCR and NPC defects. Later experiments will determine relevance of this pathway to CCR and NPC disruption in human AD and ADRDs (Aim 3). The proposed research is expected to

identify a novel physiological pathway that is essential for neuronal survival and will provide new insight into causal mechanisms of neurodegeneration that are relevant to human disease. In addition, this project has immense training potential. I will have the opportunity to improve my knowledge in neuroscience and cell biology,

and to acquire technical expertise in primary cell culture, viral construct design and transduction, mouse genetics, brain dissections and tissue preparation, and immunohistochemical analysis of human tissues. This research will be performed in a highly collaborative environment, where I will have numerous opportunities to receive

quality mentorship and training, to develop my written and presentation skills, and to grow as a mentor and teacher to more junior scientists. Overall, the Kirschstein-NRSA grant will support both my research aimed at discovering the molecular basis of neurodegeneration and my development as an independent scientist.