Fig. 3.

Mechanisms underpinning how REST and miRs interact in PD.REST is typically produced within the nucleus of DA neurons (violet) and inhibited by α-synuclein (brown). Further Lewy bodies (black) disrupt the nuclear accumulation of REST in the dopaminergic neurons and sequester REST in cytoplasm. The impairment of REST ultimately results in the decrement of PGC1-α, which in turn induces faulty mitochondrial function and impairs mitochondrial function and leads to PD (green). miR-124 blocks faulty mitochondrial function by blocking BIM and concomitant BAX translocation to mitochondria. When LPS causes inflammation during PD, the NF-kB-P65 subunit binds to the GLRX1 promoter and suppresses it. However, because miR-132 mediated NURR1 loss during inflammation cannot enlist CoREST and because transcription repression is compromised, NF-kB-p65 on the GLRX1 promoter is not removed as rapidly, resulting in GLRX1 overexpression and PD. REST knockout from astrocytes along with MPTP boost PD associated effects such as decrement in TH level and increase in neuroinflammation. Additionally, UNC0638, an inhibitor of G9a (a REST/CoREST corepressor), promotes GLRX1 overexpression by hindering the NURR1 and CoREST-mediated suppression of GLRX1. Abbreviations: DA, dopamine; PGC1-α, peroxisome proliferator-activated receptor-γ coactivator; miR-124, microRNA-124; BAX, BCL-2-like protein 4; LPS, lipopolysaccharide; GLRX1, glutaredoxin-1; CoREST, REST corepressor 1; BDNF, brain-derived neurotrophic factor; NURR1, nuclear receptor-related 1 protein; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; PD, Parkinson’s disease; TSA, Trichostatin-A; TH, tyrosine hydroxylase; miR-132, microRNA-132