Mutant Batten Disease Protein Says “No” to Unsaturated Fats

Abstract

CLN3P, the Batten's Disease Protein, Is a Novel Palmitoyl-Protein Δ-9 Desaturase Narayan SB, Rakheja D, Tan L, Pastor JV, Bennett MJ. Ann Neurol 2006;60(5):570–577. OBJECTIVE: Batten's disease, one of the most common recessively inherited, untreatable, neurodegenerative diseases of humans, is characterized by progressive neuronal loss and intraneuronal proteolipid storage. Although the gene for the disorder was cloned more than a decade ago, the function of the encoded protein, CLN3P, has not been defined thus far. METHODS: Sequence analysis using the Pfam server identified a low stringency match to a fatty acid desaturase domain in the N-terminal sequence of CLN3P. We developed a fatty acid desaturase assay based on measurement of desaturase products by gas chromatography/mass spectrometry. RESULTS: We show that CLN3P is a novel palmitoyl-protein Δ-9 desaturase, which converts membrane-associated palmitoylated proteins to their respective palmitoleated derivatives. We have further demonstrated that this palmitoyl-protein Δ-9 desaturase activity is deficient in cln3–/– mouse pancreas and is completely ablated in neuroblastoma cells by RNA inhibition. INTERPRETATION: We propose that palmitoyl-protein desaturation defines a new mechanism of proteolipid modification, and that deficiency of this process leads to the signs and symptoms of Batten's disease.