Neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive lysosomal storage diseases characterized by progressive accumulation of proteolipids (principally mitochondrial F1F0-ATP synthase and the related vacuolar proton ATPase) within the lysosomes of affected tissues and leads to retinal and neuronal degeneration, mental retardation, and early death. Accumulation of these highly hydrophobic proteins leads to the working hypothesis that NCL results from a defect in the degradation of these subunits, supported by slower rates of their degradation in primary cultures of affected individuals. The PI has recently demonstrated a mouse model for human NCL, has mapped the murine nclf gene to chromosome 9 (syntenic with human chromosome 15q), and localized it to within 0.18 cM. Exon trapping has identified 6 candidate genes within this region, with an estimated 10-25 potential additional genes present in this 350 kb nclf BAC contig. The long-term goal of the investigator is to isolate and characterize NCL genes within the mouse model. The immediate proposal is comprised of three specific aims.
Specific Aim 1 will seek to isolate and identify the nclf gene within the 350 kb nclf region of mouse chromosome 9, concentrating first on the initial six candidate genes.
Specific Aim 2 is to determine the intracellular location of the nclf gene product. This is an important first step towards elucidating its biological function.
Specific aim 3 is to investigate the role of the nclf gene product in proteolipid degradation.
