Neurodegenerative Disease Proteinopathies Are Connected to Distinct Histone Post-translational Modification Landscapes

Abstract

Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) are devastating neurodegenerative diseases involving the progressive degeneration of neurons. No cure is available for patients diagnosed with these diseases. A prominent feature of both ALS and PD is the accumulation of protein inclusions in the cytoplasm of degenerating neurons; however, the particular proteins constituting these inclusions vary: the RNA-binding proteins TDP-43 and FUS are most notable in ALS, while α-synuclein aggregates into Lewy bodies in PD. In both diseases, genetic causes fail to explain the occurrence of a large proportion of cases, and thus, both are considered mostly sporadic. Despite mounting evidence for a possible role of epigenetics in the occurrence and progression of ALS and PD, epigenetic mechanisms in the context of these diseases remain mostly unexplored. Here we comprehensively delineate histone post-translational modification (PTM) profiles in ALS and PD yeast proteinopathy models. Remarkably, we find distinct changes in histone modification profiles for each. We detect the most striking changes in the context of FUS aggregation: changes in several histone marks support a global decrease in gene transcription. We also detect more modest changes in histone modifications in cells overexpressing TDP-43 or α-synuclein. Our results highlight a great need for the inclusion of epigenetic mechanisms in the study of neurodegeneration. We hope our work will pave the way for the discovery of more effective therapies to treat patients suffering from ALS, PD, and other neurodegenerative diseases.

Restoration of histone acetylation ameliorates disease and metabolic abnormalities in a FUS mouse model

“…One important question is the molecular mechanism underlying the decrease in histone acetylation observed in Tg FUS +/+ mice. ALS-causative genes have been associated with various epigenetic modifiers and epigenetic tags [7, 12]. For example, the DNA/RNA binding protein FUS directly interacts with CBP and p300, two histone acetyltransferases, as well as with HDAC1 [72, 73].…”

Mitochondrial Dysfunction, Neurogenesis, and Epigenetics: Putative Implications for Amyotrophic Lateral Sclerosis Neurodegeneration and Treatment

“…These alterations comprise changes in phosphoacetylation of serine 10 and lysine 14 on the H3 tail (H3K14ac-S10ph), dimethylation of lysine 4 on the H3 tail (H3K4me2), and trimethylation of lysine 9 on the H3 tail (H3K9me3) ( Jimenez-Pacheco et al, 2017 ; Masala et al, 2018 ). It has also been shown that FUS can abrogate histone 4 (H4) methylation in arginine residues by inhibiting methyltransferase PRMT1 ( Tibshirani et al, 2015 ), and that overexpression of human FUS in yeast diminishes H3 acetylation in two different residues, lysine 14 and lysine 56 (H3K14 and H3K56) ( Chen K. et al, 2018 ). In addition, FUS was shown to inhibit CBP/p300 HAT after binding to it, leading to a hypoacetylation state ( Alao, 2007 ; Wang et al, 2008 ).…”

Purification of H3 and H4 Histone Proteins and the Quantification of Acetylated Histone Marks in Cells and Brain Tissue

“…Additionally, histone H3/H4 tetramer is extracted as a single, pure, and abundant fraction, enabling a reliable quantification of preserved PTMs on each of the proteins. PTMs are extremely sensitive to changes in oxidative stress and changes in pH 20,21 . Thus, in contrast to previously published methods 18 , we report an efficient strategy of rinsing the cells in serum-free media to ensure a minimum metabolic disturbance of the cells and to avoid the interference of the native PTMs with serum components.…”