CLN2 disease in an ultra-rare rapidly progresive fatal brain condition. Affected
ID: 146392 • Letter: C
Question
CLN2 disease in an ultra-rare rapidly progresive fatal brain condition. Affected children lose the ability to walk and talk around 6 y/o with death being between 8-12 yrs. CLN2 is caused by mutations resulting in deficinte activity of enzyme tripeptidyl peptidase 1 (TPP1). TPP1 carries out proteolysis using Ser/Glu/Asp triad with mechanism similar to that of ser/his/asp triad in chymotrypson. Draw mechanism by whch TPP1 cleaves generic peptide bond, clearly indicating the role of each member of the triad.
Explanation / Answer
Ans. CLN 2 (late infantile neuronal ceroid lipofuscinosis type 2) is an autosomal recessive neurodegenerative disorder which primarily affects the nervous system. It affects the children between the ages 2 to 4. In this disorder children affected by epilepsy, ataxia, myoclonus, blindness, and developmental regression. CLN2 is caused by the loss of lysosomal protease enzyme tripeptidyl peptidase1 (TPP1).
TPP1 is a serine protease enzyme which acts as a non-specific lysosomal peptidase. It generates tripeptide (Ser475/Glu272/Asp360) as a breakdown product which is produced by lysosomal proteinases. The catalytic triad (Ser475/Glu272/Asp360) in TPP1 enzyme shows that Ser475 functions as an active site nucleophile while Glu272 and Asp276 play the important role in the stabilization of the oxyanion of the tetrahedral intermediate during catalysis. TPP1 is synthesized as an inactive pro-enzyme which is proteolytically processed into the active enzyme via the targeting to the lysosome. This catalytic triad is an acidic pH optimum which is octahedrally coordinated with the Ca2+ binding site. Due to the steric constraints on the P4 substrate pocket, helps in explaining the preferential cleavage of tripeptide from the unsubstituted N terminus of proteins.
Because of the mutation in the CLN2 gene, the subunit c of mitochondrial ATP synthase gets accumulated in the subsets of neurons which leads to the cell death. Further, it will lead to the defect in lysosomal trafficking process of the TPP1 enzyme from the Golgi complex to the lysosomal complex which severely affects the metabolic pathways involved in the development of the brain.