Patients with dementing illnesses frequently complain of visual dysfunction, but given their cognitive dysfunction these symptoms may be overlooked. Though the cause of visual loss in dementing illnesses is poorly understood, it is likely that degeneration of the brain and eye share common molecular pathways. We discovered that patients with frontotemporal lobar dementia (FTLD), the most common cause of dementia in patients <60 years old, develop thinning of retinal nerve fiber layer (RNFL), indicating a loss of retinal ganglion cells (RGCs). We observed a similar phenotype in a mouse model of familial FTLD caused by loss of expression of the protein progranulin (PGRN). Using this new retinal model of FTLD, we are now able to probe previously inaccessible questions regarding FTLD pathophysiology. TDP-43 is a DNA/RNA binding protein that is normally concentrated in the nucleus. In many FTLD patients, nuclear depletion of TDP43 occurs and this loss contributes to neuron death. We found that RGCs from PGRN-knockout (KO) mice also exhibited nuclear depletion of TDP43. These cells also had impaired nuclear import of TDP43, and further study revealed that PGRN-KO RGCs with nuclear depletion of TDP43 also had loss of expression of the small GTPase Ran, a master regulator of nuclear transport. This proposal explores how loss of PGRN results in impaired Ran function, and how dysfunctional Ran- mediated nuclear transport leads to TDP43 mislocalization and RGC death.
In Aim 1, I will use microscopy and molecular biology techniques to determine how PGRN loss disrupts Ran-mediated nuclear trafficking in RGCs.
In Aim 2, I will use classic in vitro nuclear transport assays, expression approaches in primary RGCs, and in vivo rescue experiments to determine how abnormal Ran-mediated nuclear trafficking leads to TDP43 mislocalization and RGD death. A better understanding of these phenomena is a necessary first step in my long-term goal of developing novel therapies for patients with vision loss or dementia. I have a strong background in neurology and basic research and am thus well poised to carry out this project. The proposed training will take place jointly at the Gladstone Institutes and UCSF, both of which have long track records of training independent clinical-scientists. My primary mentor, Dr. Li Gan, is an expert at modeling neurodegenerative conditions in mice, and my co-mentor, Dr. Ari Green, is adept in retinal imaging techniques. I will augment their mentorship with an interdisciplinary advisory committee made up of a senior ophthalmologist (Dr. Stephen McLeod), experts in RGC biology and death (Drs. Erik Ullian and David Sretavan), an expert in the biochemical and molecular mechanisms of FTLD (Dr. Bob Farese), and a FTLD neuropathology expert (Dr. Bill Seeley). The skills gained through conducting the proposed studies in a mentored environment, combined with relevant coursework, professional development opportunities, and judicious subspecialty clinical training, will prepare me to launch my career as an independent investigator.
Individuals suffering from neurodegenerative diseases often report visual dysfunction, but how this occurs is poorly understood. To address this, we will investigate how retinal ganglion cells, which transmit visual information to the brain, become damaged in a mouse model of the neurodegenerative disease frontotemporal lobar dementia (FTLD). The ultimate goal of these studies is to develop novel diagnostics and therapies for neurodegenerative conditions causing dementia and/or vision loss.
|Ward, Michael E; Taubes, Alice; Chen, Robert et al. (2014) Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD. J Exp Med 211:1937-45|