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

Neurobiol Dis. 2019 Jul;127:362-373. doi: 10.1016/j.nbd.2019.03.025. Epub 2019 Mar 28.


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 X 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.

Keywords: 3-Hydroxy-(2,2)-dimethyl butyrate; LINCL; PPARα; TPP1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aminopeptidases / genetics
  • Aminopeptidases / metabolism*
  • Animals
  • Astrocytes / drug effects*
  • Astrocytes / metabolism
  • Brain / drug effects
  • Brain / metabolism
  • Butyrates / pharmacology*
  • Butyrates / therapeutic use
  • Cell Line
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / genetics
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / metabolism*
  • Disease Models, Animal
  • Mice
  • Mice, Knockout
  • Neuronal Ceroid-Lipofuscinoses / drug therapy
  • Neuronal Ceroid-Lipofuscinoses / genetics
  • Neuronal Ceroid-Lipofuscinoses / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • PPAR alpha / metabolism*
  • Serine Proteases / genetics
  • Serine Proteases / metabolism*
  • Tripeptidyl-Peptidase 1
  • Up-Regulation


  • Butyrates
  • PPAR alpha
  • Tpp1 protein, mouse
  • Tripeptidyl-Peptidase 1
  • Serine Proteases
  • Aminopeptidases
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases