Batten Disease, a group of inherited neurodegenerative lysosomal storage diseases, leads to blindness, seizures, and premature death. The storage products accumulate in many different tissues including neurons, epithelial cells, smooth muscle cells, lymphocytes, and fibroblasts. While several different cellular components accumulate in lysosomes from Batten Disease patients, the most abundant material is a single protein, the very hydrophobic subunit 9 of mitochondrial ATP synthase. The problem in Batten Disease may be mistargeting of a fraction of newly synthesized subunit 9 to lysosomes. Alternatively, subunit 9 may enter lysosomes only during the uptake of entire mitochondria by autophagy. In this case, the striking accumulation of this protei in lysosomes suggests a defect in the intralysosomal degradation of this hydrophobic protein.
The aims of the work proposed here are to: 1) determine whether either of the two subunit 9 precursors are significantly mistargeted to lysosomes; 2) analyze the ability of lysosomes to degrade internalized ATP synthase subunit 9; and 3) establish whether accumulation of ATP synthase subunit 9 is likely to be the primary defect in Batten Disease.
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