LMK235, a small molecule inhibitor of HDAC4/5, protects dopaminergic neurons against neurotoxin- and α-synuclein-induced degeneration in cellular models of Parkinson's disease

• DOI: 10.1016/j.mcn.2021.103642
• Publication Date: 2021-06-10T08:18:25Z
• Authors: Martina Mazzocchi; Susan R. Goulding; Sean L. Wyatt; Louise M. Collins; Aideen M. Sullivan; Gerard W. O'Keeffe
• Keywords: Neurite; Trichostatin A; HDAC6

Epigenetic modifications in neurodegenerative disease are under investigation for their roles progression. Alterations acetylation rates of certain Parkinson's (PD)-linked genes have been associated with the pathological progression this disorder. In light this, and given lack disease-modifying therapies PD, HDAC inhibitors (HDIs) consideration as potential pharmacological agents. The neuroprotective effects pan-HDACs some class-specific tested vivo vitro models varying outcomes. Here we used gene co-expression analysis to identify HDACs that human dopaminergic (DA) neuron development. We identified HDAC3, HDAC5, HDAC6 HDAC9 being highly correlated DA markers, SLC6A3 NR4A2. RT-qPCR revealed mRNA expression these exhibited similar temporal profiles during embryonic mouse midbrain (mDA) a number small molecule HDIs on SH-SY5Y cells, using neurite growth phenotypic readout neurotrophic action. Neither class I-specific HDIs, RGFP109 RGFP966, nor inhibitor ACY1215, had significant outgrowth. However, IIa HDI, LMK235 (a HDAC4/5 inhibitor), significantly increased histone found BMP-Smad-dependent transcription cells was required its growth-promoting neurons primary cultures day (E) 14 rat ventral mesencephalon (VM). These were also seen transfected HDAC5 siRNA. Furthermore, treatment exerted against degeneration induced by neurotoxin 1-methyl-4-phenylpyridinium (MPP+), both cultured neurons. Treatment axonal overexpression wild-type (WT) or A53T mutant α-synuclein summary, data show LMK235, cell relevance PD.