Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis

Gustavo H.B. Maegawa, Michael Tropak, Justin Buttner, Tracy Stockley, Fernando Kok, Joe T.R. Clarke, Don J. Mahuran

Research output: Contribution to journalArticlepeer-review

120 Scopus citations


Late-onset GM2 gangliosidosis is composed of two related, autosomal recessive, neurodegenerative diseases, both resulting from deficiency of lysosomal, heterodimeric β-hexosaminidase A(Hex A, αβ). Pharmacological chaperones (PC) are small molecules that can stabilize the conformation of a mutant protein, allowing it to pass the quality control system of the endoplasmic reticulum. To date all successful PCs have also been competitive inhibitors. Screening for Hex A inhibitors in a library of 1040 Food Drug Administration-approved compounds identified pyrimethamine (PYR (2,4-diamino 5-(4-chlorophenyl)-6-ethylpyrimidine)) as the most potent inhibitor. Cell lines from 10 late-onset Tay-Sachs (11 α-mutations, 2 novel) and 7 Sandhoff (9 β-mutations, 4 novel) disease patients, were cultured with PYR at concentrations corresponding to therapeutic doses. Cells carrying the most common late-onset mutation, αG269S, showed significant increases in residual Hex A activity, as did all 7 of the β-mutants tested. Cells responding to PC treatment included those carrying mutants resulting in reduced Hex heat stability and partial splice junction mutations of the inherently less stable α-subunit. PYR, which binds to the active site in domain II, was able to function as PC even to domain I β-mutants. We concluded that PYR functions as a mutation-specific PC, variably enhancing residual lysosomal Hex A levels in lateonset GM2 gangliosidosis patient cells.

Original languageEnglish (US)
Pages (from-to)9150-9161
Number of pages12
JournalJournal of Biological Chemistry
Issue number12
StatePublished - Mar 23 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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