Upregulation of tripeptidyl-peptidase 1 by 3-hydroxy-(2,2)-dimethyl butyrate, a brain endogenous ligand of PPAR?: Implications for late-infantile Batten disease therapy.

ABSTRACT: The late-infantile Batten disease or late-infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive lysosomal storage disorder caused by mutations in the Cln2 gene leading to deficiency of lysosomal enzyme tripeptidyl peptidase 1 (TPP1). At present, available options for this fatal disorder are enzyme replacement therapy and gene therapy, which are extensively invasive and expensive. Our study demonstrates that 3-hydroxy-(2,2)-dimethyl butyrate (HDMB), a brain endogenous molecule, is capable of stimulating TPP1 expression and activity in mouse primary astrocytes and a neuronal cell line. HDMB activated peroxisome proliferator-activated receptor-? (PPAR?), which, by forming heterodimer with Retinoid X receptor-? (RXR?), transcriptionally upregulated the Cln2 gene. Moreover, by using primary astrocytes from wild type, PPAR?-/- and PPAR?-/- mice, we demonstrated that HDMB specifically required PPAR? for inducing TPP1 expression. Finally, oral administration of HDMB to Cln2 heterozygous (Cln2+/-) mice led to a marked upregulation of TPP1 expression in the motor cortex and striatum in a PPAR?-dependent fashion. Our study suggests that HDMB, a brain endogenous ligand of PPAR?, might have therapeutic importance for LINCL treatment.

SUBMITTER: Chakrabarti S 

PROVIDER: S-EPMC6588492 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature