Molecular insights into <scp>α‐synuclein</scp> interaction with individual human core histones, linker histone, and <scp>dsDNA</scp>

Jos, Sneha; Gogoi, Hemanga; Prasad, Thazhe Kootteri; Hurakadli, Manjunath A.; Kamariah, Neelagandan; Padmanabhan, Balasundaram; Padavattan, Sivaraman

doi:10.1002/pro.4167

Cited by 13 publications

(8 citation statements)

References 45 publications

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“…In fact, we expect the local nucleic acid concentration to be higher in the nucleus, suggesting that the effects measured should be even stronger. Also, aS was shown to localize in the nucleus of the cells 76,77 , associated with nucleic acids 16,78 , nucleosomes 79 and processing bodies 46 , but no proof of direct and functional RNA binding effects on aggregation have been so far carried out. While Siegert and colleagues have shown RNA has little effect and can actually abrogate aS phase separation 47 , the molecular aspects of the effect of RNA on aS aggregation was not characterized.…”

Section: Discussionmentioning

confidence: 99%

A Computational Approach Reveals the Ability of Amyloids to Sequester RNA: the Alpha Synuclein Case

Rupert

Monti

Zacco

et al. 2022

Preprint

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The modulating effect of nucleic acids on protein aggregation has recently come into the spotlight, with RNA shown to either prevent or promote protein assembly depending on the molecular context. Here, we computed the biophysical properties of amyloids and observed a trend indicating that regions outside the aggregates core are highly prone to interact with nucleic acids. In the case of alpha synuclein (aS), an intrinsically disordered protein abundantly expressed in the brain, found in the nucleus and involved in Parkinson's disease, our predictions indicate that regions outside the aggregate are able to contact RNA, but the acidic C-terminal prevents the formation of stable interactions. We performed aggregation assays with both the wild type alpha-synuclein (aS140) as well as a C-terminally truncated isoform (aS103) and found that while RNA increases the aggregation rate of aS103, it decreases that of aS140, although at higher RNA concentrations the trend is inverted. To further elucidate the effects driving this behavior, we built a general dynamic model that describes the aggregation process of monomers in the presence of RNA. Our predictions indicate that RNA affects aS103 and aS140 aggregation in a non-linear manner and prioritize the interaction between RNA and aggregate as the most relevant. To confirm this, we extracted RNA from aS103 and aS140 aggregates and observed that they indeed acquire distinct RNA-sequestering abilities. Our research demonstrates that binding to transcripts can drastically alter the aggregation of a protein and represents an important gain-of-function mechanism to be further investigated.

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Section: Discussionmentioning

confidence: 99%

A Computational Approach Reveals the Ability of Amyloids to Sequester RNA: the Alpha Synuclein Case

Rupert

Monti

Zacco

et al. 2022

Preprint

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“…Although αSyn was given its name due to its synaptic (syn-) and nuclear (-nuclein) localization [ 218 ], its function in the nucleus remains poorly understood. However, various studies have proposed that αSyn could interact directly with the DNA double helix, histones, and other nuclear proteins, participating in both genetic and epigenetic regulation of gene expression [ 219 , 220 , 221 , 222 , 223 , 224 ]. Initial evidence of αSyn potential pathogenic impact on the cell nucleus arose from postmortem observations of αSyn nuclear inclusions in neurons and glial cells in patients with MSA [ 225 ].…”

Section: αSyn-induced Toxicity In Distinct Organellesmentioning

confidence: 99%

Alpha-Synuclein Contribution to Neuronal and Glial Damage in Parkinson’s Disease

Saramowicz,

Siwecka,

Galita

et al. 2023

IJMS

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Parkinson’s disease (PD) is a complex neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the widespread accumulation of alpha-synuclein (αSyn) protein aggregates. αSyn aggregation disrupts critical cellular processes, including synaptic function, mitochondrial integrity, and proteostasis, which culminate in neuronal cell death. Importantly, αSyn pathology extends beyond neurons—it also encompasses spreading throughout the neuronal environment and internalization by microglia and astrocytes. Once internalized, glia can act as neuroprotective scavengers, which limit the spread of αSyn. However, they can also become reactive, thereby contributing to neuroinflammation and the progression of PD. Recent advances in αSyn research have enabled the molecular diagnosis of PD and accelerated the development of targeted therapies. Nevertheless, despite more than two decades of research, the cellular function, aggregation mechanisms, and induction of cellular damage by αSyn remain incompletely understood. Unraveling the interplay between αSyn, neurons, and glia may provide insights into disease initiation and progression, which may bring us closer to exploring new effective therapeutic strategies. Herein, we provide an overview of recent studies emphasizing the multifaceted nature of αSyn and its impact on both neuron and glial cell damage.

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“…αS binds to the N-terminal flexible tails of histones H3, H4, and H1 [ 80 ]. Its fibrillation is accelerated by H1 released from the nucleus during apoptosis [ 81 ].…”

Section: Interaction Between αS and Epigenetic Factorsmentioning

confidence: 99%

Unraveling the Complex Interplay between Alpha-Synuclein and Epigenetic Modification

Sugeno

Hasegawa

2023

IJMS

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Alpha-synuclein (αS) is a small, presynaptic neuronal protein encoded by the SNCA gene. Point mutations and gene multiplication of SNCA cause rare familial forms of Parkinson’s disease (PD). Misfolded αS is cytotoxic and is a component of Lewy bodies, which are a pathological hallmark of PD. Because SNCA multiplication is sufficient to cause full-blown PD, gene dosage likely has a strong impact on pathogenesis. In sporadic PD, increased SNCA expression resulting from a minor genetic background and various environmental factors may contribute to pathogenesis in a complementary manner. With respect to genetic background, several risk loci neighboring the SNCA gene have been identified, and epigenetic alterations, such as CpG methylation and regulatory histone marks, are considered important factors. These alterations synergistically upregulate αS expression and some post-translational modifications of αS facilitate its translocation to the nucleus. Nuclear αS interacts with DNA, histones, and their modifiers to alter epigenetic status; thereby, influencing the stability of neuronal function. Epigenetic changes do not affect the gene itself but can provide an appropriate transcriptional response for neuronal survival through DNA methylation or histone modifications. As a new approach, publicly available RNA sequencing datasets from human midbrain-like organoids may be used to compare transcriptional responses through epigenetic alterations. This informatic approach combined with the vast amount of transcriptomics data will lead to the discovery of novel pathways for the development of disease-modifying therapies for PD.

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Molecular insights into α‐synuclein interaction with individual human core histones, linker histone, and dsDNA

Cited by 13 publications

References 45 publications

A Computational Approach Reveals the Ability of Amyloids to Sequester RNA: the Alpha Synuclein Case

A Computational Approach Reveals the Ability of Amyloids to Sequester RNA: the Alpha Synuclein Case

Alpha-Synuclein Contribution to Neuronal and Glial Damage in Parkinson’s Disease

Unraveling the Complex Interplay between Alpha-Synuclein and Epigenetic Modification

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