Neuroprotection and lifespan extension in Ppt1(-/-) mice by NtBuHA: therapeutic implications for INCL.
Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating childhood neurodegenerative lysosomal storage disease (LSD) that has no effective treatment. It is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 deficiency impairs the cleavage of thioester linkage in palmitoylated proteins (constituents of ceroid), preventing degradation by lysosomal hydrolases. Consequently, accumulation of lysosomal ceroid leads to INCL. Thioester linkage is cleaved by nucleophilic attack. Hydroxylamine, a potent nucleophilic cellular metabolite, may have therapeutic potential for INCL, but its toxicity precludes clinical application. We found that a hydroxylamine derivative, N-(tert-Butyl) hydroxylamine (NtBuHA), was non-toxic, cleaved thioester linkage in palmitoylated proteins and mediated lysosomal ceroid depletion in cultured cells from INCL patients. In Ppt1(-/-) mice, which mimic INCL, NtBuHA crossed the blood-brain barrier, depleted lysosomal ceroid, suppressed neuronal apoptosis, slowed neurological deterioration and extended lifespan. Our findings provide a proof of concept that thioesterase-mimetic and antioxidant small molecules such as NtBuHA are potential drug targets for thioesterase deficiency diseases such as INCL.
1] Section on Developmental Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA. [2].
Chinmoy
C
Sarkar
Goutam
G
Chandra
Shiyong
S
Peng
Zhongjian
Z
Zhang
Aiyi
A
Liu
Anil B
AB
Mukherjee
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002247:Carbon Isotopes / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006898:Hydroxylamines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D008136:Longevity / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009472:Neuronal Ceroid-Lipofuscinoses / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use*; D010171:Palmitoyl Coenzyme A / Q000187:drug effects / Q000378:metabolism; D013869:Thiolester Hydrolases / Q000172:deficiency*; D013997:Time Factors
D002247:Carbon Isotopes; D006898:Hydroxylamines; C585287:N-(tert-butyl)hydroxylamine; D018696:Neuroprotective Agents; D010171:Palmitoyl Coenzyme A; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase