The Section on Developmental Genetics conducts laboratory and clinical investigations into neurodegenerative, inflammatory, and autoimmune disorders. Our research currently focuses on understanding the molecular mechanisms of pathogenesis of a group of hereditary childhood neurodegenerative lysosomal storage disorders called neuronal ceroid lipofuscinosis (NCL), commonly known as Batten disease. Mutations in eight genes cause various types of NCLs. Currently, there are no effective treatments for any of the NCLs. The infantile NCL or INCL is an autosomal recessive disease caused by mutations in the CLN1 gene, which encodes a lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1). PPT1 catalyzes the cleavage of thioester linkage in palmitoylated (S-acylated) proteins (constituent of ceroid), facilitating their degradation in lysosomes. Thus, PPT1 deficiency causes accumulation of ceroid in lysosomes, leading to INCL pathogenesis. Children afflicted with INCL are normal at birth but, by 11 to 18 months of age, exhibit signs of psychomotor retardation. By 2 years of age, they are completely blind due to retinal degeneration and, by the age 4, manifest no brain activity and remain in a vegetative state for 6 to 8 years before eventual death. These grim outcomes underscore the urgent need for the development of rational and effective therapeutic strategies not only for INCL but also for all NCLs.
The aim of our clinical studies is to apply the knowledge gained from our laboratory investigations to develop novel therapeutic strategies for Batten disease. The results of our earlier investigations led to a bench-to-bedside clinical trial that is currently under way. Using CNL1-knockout (PPT1-KO) mice, which recapitulate virtually all clinical and pathological features of INCL, we discovered that PPT1 deficiency causes endoplasmic reticulum (ER) and oxidative stress, which at least in part causes neuronal death by apoptosis. We also delineated a mechanism by which PPT1 deficiency disrupts the recycling of the synaptic vesicle (SV) proteins, which are essential for regenerating fresh SVs to replenish the SV pool size at the nerve terminals in order to maintain uninterrupted neurotransmission. During the past year, we demonstrated that ER and oxidative stresses mediate neuronal apoptosis and neuroinflammation. Further, we showed that omega-3 and omega-6 fatty acids suppress ER and oxidative-stress in cultured neurons and neuronal progenitor cells from PPT1-KO mice, suggesting that these fatty acids may have therapeutic potential. We also discovered that nucleophilic small molecules with antioxidant properties ameliorate the neurological abnormalities in PPT1-KO mice and extend their lifespan. These and other related studies (uteroglobin, IgA nephropathy, etc.) provide insight into the complex mechanisms of heritable disorders of neurodegeneration, inflammation, and autoimmune diseases and identify several potential therapeutic targets. Our ongoing laboratory and clinical investigations have advanced our knowledge of these diseases. We plan to apply new findings from our laboratory to develop novel therapeutic approaches not only for INCL but also for other related diseases.