Upregulation of tripeptidyl-peptidase 1 by 3-hydroxy-(2,2)-dimethyl butyrate, a brain endogenous ligand of PPARα: 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-α (PPARα), which, by forming heterodimer with Retinoid × receptor-α (RXRα), transcriptionally upregulated the Cln2 gene. Moreover, by using primary astrocytes from wild type, PPARα −/− and PPARβ −/− mice, we demonstrated that HDMB specifically required PPARα 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 PPARα-dependent fashion. Our study suggests that HDMB, a brain endogenous ligand of PPARα, might have therapeutic importance for LINCL treatment.

Treadmill exercise reduces α-synuclein spreading via PPARα

“…Next, we evaluated the mRNA expression of 22 genes that are involved in autophagy-lysosomal functioning ( Figure S7A ). The majority of these genes were previously reported to be directly regulated by TFEB ( Martini-Stoica et al, 2016 ; Settembre et al, 2012 ), whereas CLN2 and NPC expression can be directly regulated by PPARα ( Chakrabarti et al, 2019 ; Ghosh and Pahan, 2016 ). The dendrogram demonstrates that the gene cluster containing the genes LC3B, SQSTM1, cathepsin B, cathepsin D , and LAMP1 had the highest up-regulated genes in A53T R mice compared with the A53T NR group.…”

Identification of a TPP1 Q278X Mutation in an Iranian Patient with Neuronal Ceroid Lipofuscinosis 2: Literature Review and Mutations Update

“…Transport to the lysosome is enabled by mannose-6-phosphate receptor binding. At the lysosome, CLN2 is first further processed into a 50 kDa polypeptide followed by cleavage into the mature 368 amino acid (48 kDa) enzyme by lysosomal exoglycosidases such as neuraminidases [ 19 , 20 , 21 ]. Lysosomal degradation pathways involving TPP1 are summarized in Figure 2 .…”