Deregulated Nrf2-Keap1-BACH1 axis in autism spectrum disorder

Very important study: This research shows that in ASD (autism), Nrf2 is chronically upregulated, but it doesn’t lead to the consequent upregulation of some key targets like HO-1, because BACH1 inhibits them.

This finding essentially demonstrates that Nrf2 activation doesn’t necessarily lead to the normal activation of all its targets. Some are activated (like KEAP1, which traps Nrf2 by design, and BACH1, which competes with Nrf2), while others are not (like HO-1).

The reason BACH1 remains in the nucleus and interferes with Nrf2’s normal function is insufficient heme in the nucleus. Heme binds to BACH1 and leads to its export from the nucleus, allowing Nrf2 to do its job.

This is another reminder of why treating iron deficiency is important in TS. Chronic selective Nrf2 overactivation is likely the reason tics develop - some proteins are upregulated and interfere with others (like excess p62, which prevents GABA receptor expression and blocks Gephyrin function), while others can’t start working to clear out stress.

Quote from the study:

Our results revealed constitutive activation of Nrf2, accompanied by reduced expression of its downstream target heme oxygenase-1 (HO1) and marked nuclear accumulation of the transcriptional repressor BACH1 in ASD cells.

Moreover, ASD fibroblasts failed to increase Nrf2 nuclear translocation upon sulforaphane (SFN) stimulation, a response consistent with elevated basal levels of Keap1, a negative regulator that sequesters Nrf2 in the cytoplasm.

Notably, treatment with hemin, known to induce nuclear export and degradation of BACH1, successfully restored HO1 gene and protein expression and ameliorated impaired mitochondrial function in ASD fibroblasts, as suggested by the decrease of mtROS levels and the restored mitochondrial membrane potential.