| First Author | Chakrabarti S | Year | 2019 |
| Journal | Neurobiol Dis | Volume | 127 |
| Pages | 362-373 | PubMed ID | 30928643 |
| Mgi Jnum | J:279754 | Mgi Id | MGI:6355795 |
| Doi | 10.1016/j.nbd.2019.03.025 | Citation | Chakrabarti S, et al. (2019) Upregulation of tripeptidyl-peptidase 1 by 3-hydroxy-(2,2)-dimethyl butyrate, a brain endogenous ligand of PPARalpha: Implications for late-infantile Batten disease therapy. Neurobiol Dis 127:362-373 |
| abstractText | 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-alpha (PPARalpha), which, by forming heterodimer with Retinoid X receptor-alpha (RXRalpha), transcriptionally upregulated the Cln2 gene. Moreover, by using primary astrocytes from wild type, PPARalpha(-/-) and PPARbeta(-/-) mice, we demonstrated that HDMB specifically required PPARalpha 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 PPARalpha-dependent fashion. Our study suggests that HDMB, a brain endogenous ligand of PPARalpha, might have therapeutic importance for LINCL treatment. |
