Fig 2: Proposed mechanism for DMF therapeutic efficacy in managing HD-induced motor dysfunction. DMF ameliorates striatal loss of neurons in a 3-NP induced HD model by 1) inducing AKT/mTOR activation to inhibit intrinsic apoptosis caused by both ER stress arms IRE1α/JNK and PERK/CHOP/GADD153 activation; 2) activating the BDNF/TrkB/AKT/CREB axis to overweigh the pro-survival Bcl-2 and enhance DA formation; 3) downregulating miRNA-634 to initiate AKT activation; and 4) suppressing the oxidative stress response consequent to CHOP/GADD153 inhibition to additionally suppress intrinsic apoptosis. AKT, protein kinase B, Bax, B-cell lymphoma-2-associated X; Bcl-2, B-cell lymphoma-2; BDNF, brain-derived neurotrophic factor; CHOP/GADD153, C/EBP homologous protein; CREB, cAMP response element-binding protein; DA, dopamine; DMF, dimethyl fumarate; DR, dopamine receptor; HD, Huntington’s disease; IRE1α, inositol-requiring enzyme 1 alpha; JNK, c-Jun NH2-terminal kinase; miRNA-634, microRNA-634; mTOR, mammalian target of rapamycin; 3-NP, 3-nitropropionic acid; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PERK, protein kinase R-like endoplasmic reticulum kinase; ROS, reactive oxygen species; TH, tyrosine hydroxylase; TrkB, tropomyosin receptor kinase B. This figure is created in BioRender.com.