The identification of TBK1
is exciting for understanding ALS pathogenesis, especially since the inflammatory and autophagy pathways have been previously implicated in the disease," said Lucie Bruijn of the ALS Association.
After sorting the genes by their predicted biological proximity to TLR3, Itan and his colleagues found TBK1
at the top of the list of genes in both patients.
Amlexanox appears to work in mice by inhibiting two genes -- IKKE and TBK1
-- that we think together act as a sort of brake on metabolism," Saltiel said.
Investigators showed that all six plant compounds target an enzyme known as TBK1
At least three distinct pathways are activated through various adapter complexes interacting with TLR4, the MAP kinase pathway resulting in activation of p38 and JNK, the IKK complex resulting in activation of the nuclear factor-kB (NF-kB) pathway and activation of the interferon regulatory factors IRF-3 and IRF-7 through TBK1
(O'Neill and Bowie, 2007).
As a result, different cellular kinases, including the IRF3 kinases TBK1
and IKK[epsilon], become activated.