Histone Acetylation Changes May Contribute to Parkinson’s

Histone Acetylation, Parkinson’s-Parkinson’s-Disease

The origin of Parkinson’s disease is frustratingly vague, an ambiguous cocktail of biological and environmental puzzle pieces which defies any simple fix. In a May 2016 study, a team of scientists began to explore whether epigenetic modification could hold the key to Parkinson’s pathology.

The group analyzed the chemical variants of core histone molecules involved in a Parkinson’s patient’s DNA organization, hoping to uncover suspicious changes in gene regulation. At the experiment’s close, the researchers successfully identified altered regulation patterns- physiological anomalies which could potentially become biomarkers for the development of more effective Parkinson’s treatments [1].

The Histone Hypothesis

Parkinson’s is a neurodegenerative brain disorder diagnosed according to a triad of symptoms: increasing motor difficulties, neuron loss in the substantia nigra brain region, and Lewy body (atypical protein clump) formation. The substantia nigra is a sheet of highly pigmented neurons responsible for production of dopamine, a neurotransmitter critical to movement facilitation. When cells in this territory die, dopamine becomes increasingly inconsistent and the Parkinson’s patient exhibits the disease’s characteristic motor dysfunction [2].

The Lewy body is composed largely of the protein alpha-synuclein which appears to reduce acetylation of histone H3 until a given cell sputters to its death [1]. Why is histone’s level of acetylation significant to Parkinson’s research? Since histones are the core molecules which wind long DNA strands into orderly units, they dictate how compactly a DNA molecule will be coiled. Amplified acetylation has been correlated with gentler histone grasp and increased gene expression [3]. 

Parkinson’s apparent histone acetylation decline could therefore indicate decreased gene expression, a phenomenon bearing possible ties to the disease’s detrimental brain cell deterioration. For a while, research had only confirmed such instances in brain areas that were already conquered by the disease. But the research team set out to explore histone H3 acetylation within the primary motor cortex of Parkinson’s patients, one of the last brain regions to succumb to the disease’s inexorable march. Drawing upon prior documentation, the researchers hypothesized that they would uncover a similarly diminished net presence of histone H3 acetylation [1].

Tracking Acetylation

They obtained primary motor cortex tissue samples from both diseased and healthy brains for the purpose of controlled comparison. All of the samples were chemically stained to highlight the degree of substantia nigra cell breakdown and the prevalence of Lewy bodies. As expected, the Parkinson’s samples were scarred by these disease red-flags while the healthy samples returned clear results.

This preliminary step simply confirmed the biological dichotomy between the experimental and control groups. Afterward, the samples were subjected to subsequent staining which illuminated the acetylation levels of multiple histone H3 variants:  H3K9, H3K14, H3K18, and H3K23. Each histone version is naturally acetylated at a different molecular location, resulting in unique pattern of chemical function. The net histone H3 acetylation level would be defined as a sum of these individual levels [1].

Surprising Results

Histone H3K23 presented relatively similar levels in Parkinson’s and non-Parkinson’s samples alike, offering no contribution in either direction. But the researchers unexpectedly discovered that there was still an overall net increase in histone H3 acetylation due to spikes in both H3K14 and H3K18 acetylation levels. This contradicted the experimenters’ beginning hypothesis and actually suggested enhanced gene expression. H3K9 was the only histone H3 in question to display an acetylation decrease; struggling to resolve this conflict, they concluded that there was likely an overarching rise in gene expression which was dampened only slightly by the opposing force of residual gene repression. Why this was the case, they still could not entirely explain [1].


The results remain inconclusive. Why did the Parkinson’s primary motor cortex possess increasingly acetylated histones? Brainstorming yielded two possibilities: perhaps it was how the cells reacted to neurodegeneration or perhaps it was the cells’ form of self-fortification against neurodegeneration. Both explanations are equally plausible, yet the scale is tipped slightly toward the court of the self-fortification theory. Other studies involving treatment with histone deacetylase inhibitors, enzymes which prevent the removal of acetyl groups and therefore increase overall acetylation levels, have demonstrated the inhibitors’ protective effects.

The next step forward will be to examine acetylation levels throughout brain regions that are affected at even earlier disease stages. Histone deacetylase inhibitors may eventually be the next secret weapons in the arsenal against Parkinson’s disease [1].




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    By: Avigail Goldberger

    Avigail Goldberger is an avid science devotee, with a particular interest in biology, genetics, and neuroscience. Her love of STEM subjects is equally matched by a passion for literature and writing, so she hopes that her eventual profession will synthesize her multifaceted academic drives.

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