Most metabolic diseases, including two-thirds of lysosomal storage disorders (LSD) affect the brain. For many, including Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), it is not known how the biochemical defect induces central nervous system dysfunction. Studies have focused on cellular-level pathology, with few investigations of how metabolic defects disrupt functional neuronal circuits. Ultimately, disruption of brain networks leads to the symptoms, such as seizures and neurocognitive regression, that are devastating to patients. JNCL results from biallelic mutations in CLN3. How loss of CLN3 protein disrupts neurologic function is unclear. In preliminary work, I have demonstrated that JNCL mice, like human patients, have abnormal electroencephalograms, suggesting mice are a suitable model for circuit-level studies. On autopsy, JNCL brains show neurodegeneration and lysosomal storage accumulation; the hippocampus is especially vulnerable. In my preliminary voltage-sensitive dye imaging (VSDI) studies of the JNCL mouse hippocampus, I have found progressive changes in excitability. Also, recent studies of late-stage JNCL show synaptic dysfunction in the mouse hippocampus. However, in studies of late-stage disease it is impossible to parse which changes are due to the primary loss of CLN3 protein or secondary to widespread neuropathology. Gene and/or enzyme replacement therapy is being developed for many LSDs. While this is exciting, moving to gene-based treatment before we know if replacement will fix the patients is problematic. Where and when to rescue protein expression is unclear. A major unanswered question is if correction of the biochemical defect underlying a metabolic disease will rescue the function of neuronal networks and improve symptoms. My central hypothesis is that in JNCL, hippocampal circuit pathology arises from synaptic dysfunction induced by loss of CLN3 protein. Because of the development of abnormal network dynamics, a vulnerable window may exist beyond which correction of single cell biochemistry will not correct functional defects. I will evaluate this by: 1) defining circuit level pathology using VSDI in two JNCL models; 2) exploring the synaptic and cellular changes driving network changes, and 3) assessing if rescue of CLN3 expression at different stages of disease can rescue circuit and synaptic dynamics. This work has important implications for future studies of the basic science of the CLN3 protein and novel therapies for JNCL. As an MD/PhD, I am passionate about translating basic science discoveries into new therapies for my patients with neurometabolic disorders. My mentors Dr. Eric Marsh, a physician-scientist neurogeneticist and electrophysiologist, and Dr. Beverly Davidson, a lysosomal storage disease expert, have devoted their careers to this goal. Under their guidance, I will use this 5-year experience to learn to apply my electrophysiology skills to studies of the brain and to prepare for a career as an independent R01-funded translational researcher.
Lysosomal storage disorders (LSDs) are multi-system, progressive metabolic diseases that affect approximately 1 in 7000 individuals, and although two-thirds of LSD patients have significant neurologic symptoms, most currently-available LSD therapies fail to improve the central nervous system manifestations of disease. Juvenile neuronal ceroid lipofuscinosis (JNCL), is an untreatable, progressive neurologic LSD and the most common cause of childhood dementia. In this application, I propose to study both the synaptic and circuit-level pathology of JNCL; this approach of considering LSDs, such as JNCL, as both biochemical defects and disorders of neural circuits is novel and could provide important insights for future therapy development.
