Cellular Pathology of Batten Disease

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DESCRIPTION (provided by applicant): The purpose of this proposal is to gain a better understanding of the cellular mechanisms leading to pathological changes and functional deficits in infantile neuronal ceroid lipofuscinoses (INCL). Although the clinical phenotype is well documented in patients with INCL, little is known about how changes in the cytoarchitecture of the central nervous system (CMS) give rise to the severe cognitive, motor, physiological, and sensory deficits associated with this disease. By systematically investigating the neuronal and glial pathology and its relationship with functional changes in INCL, a greater understanding of disease pathogenesis can occur. Since INCL results from a global deficiency in the enzyme palmitoyl protein thioesterase 1 (PPT1), it remains unclear how the underlying cellular pathology in both glia or neurons leads to physiological deficits and behavioral impairment. With recent data demonstrating that astrocyte activation precedes neurodegeneration in a mouse model of INCL, we hypothesize that astrocyte dysfunction leads to functional changes in the PPT1 deficient (-/-) mice. We will test this hypothesis by selectively restoring PPT1 activity within astrocytes in PPT1-/- mice. Due to the principle of 'cross correction', traditional gene transfer and transgenic approaches cannot be employed. Therefore, we will use a lysosomal membrane- tethered form of PPT1 (PPT1-LAMP) in combination with cell specific promoters to achieve selective PPT1 expression in transgenic mice. This novel approach will provide a useful tool to investigate the cellular mechanisms contributing to pathological and functional changes in INCL. No treatment is currently available for INCL. As a class of disorders, neuronal ceroid lipofuscinoses (NCLs) represent one the most common forms of inherited pediatric neurodegenerative disorders worldwide with INCL being the most devastating form of these diseases. By gaining a greater understanding of the disease process in the CNS of patients with INCL, more efficacious and better targeted therapies can be developed for the treatment of INCL. This will not only help improve the standard of care of these patients but also help alleviate the pain, suffering, and cost of care for patient's families.