Nuclear localization and phosphorylation modulate pathological effects of alpha-synuclein

Abstract

Alpha-synuclein (aSyn) is a central player in Parkinson's disease (PD) but the precise molecular mechanisms underlying its pathogenicity remain unclear. It has recently been suggested that nuclear aSyn may modulate gene expression, possibly via interactions with DNA. However, the biological behavior of aSyn in the nucleus and the factors affecting its transcriptional role are not known. Here, we investigated the mechanisms underlying aSyn-mediated transcription deregulation by assessing its effects in the nucleus and the impact of phosphorylation in these dynamics. We found that aSyn induced severe transcriptional deregulation, including the downregulation of important cell cycle-related genes. Importantly, transcriptional deregulation was concomitant with reduced binding of aSyn to DNA. By forcing the nuclear presence of aSyn in the nucleus (aSyn-NLS), we found the accumulation of high molecular weight aSyn species altered gene expression and reduced toxicity when compared to the wild-type or exclusively cytosolic protein. Interestingly, nuclear localization of aSyn, and the effect on gene expression and cytotoxicity, was also modulated by phosphorylation on serine 129. Thus, we hypothesize that the role of aSyn on gene expression and, ultimately, toxicity, may be modulated by the phosphorylation status and nuclear presence of different aSyn species. Our findings shed new light onto the subcellular dynamics of aSyn and unveil an intricate interplay between subcellular location, phosphorylation, and toxicity, opening novel avenues for the design of future strategies for therapeutic intervention in PD and other synucleinopathies.

Effects of alpha‐synuclein post‐translational modifications on metal binding

“…In contrast, in brains of patients that suffered from synucleinopathies and in animal models of these diseases, the majority of AS is phosphorylated on Ser129 (Okochi et al ; Kahle et al ; Fujiwara et al ; Takahashi et al ; Anderson et al ). Currently, we still do not fully understand the role of Ser129 phosphorylation on AS function, but it appears to regulate its structure, membrane binding, aggregation, neurotoxicity and, more recently, subcellular distribution (Fujiwara et al ; Anderson et al ; Gonçalves and Outeiro ; Pinho et al ).…”

“…It has been shown that this PTM could induce a structurally distinct and functionally more toxic strain of AS (Ma et al ). Nevertheless, Ser129 phosphorylation might also play a role in the regulation of normal AS function (Pinho et al ).…”

Circulating Brain‐Enriched MicroRNAs for Detection and Discrimination of Idiopathic and Genetic Parkinson's Disease

“…Although disease‐causing mutations are only found in 2% of patients, they provide important insights into the pathogenesis of PD. Alpha‐synuclein (SNCA) is a neuronal protein, with pleiotropic functions, central to the disease process. Point mutations, gene duplication, and triplication events in the SNCA locus have been identified in families with autosomal dominant early‐onset PD .…”

Glial α‐synuclein promotes neurodegeneration characterized by a distinct transcriptional program in vivo

“…We have previously reported that nuclear α-synuclein inhibits histone acetylation (Kontopoulos, Parvin, & Feany, 2006), and this inhibition would be expected to decrease transcription. Others have reported direct interactions between α-synuclein and histones (Goers et al, 2003) or DNA (Siddiqui et al, 2012), as well as wide-ranging transcriptional deregulation (Pinho et al, 2019). α-Synuclein-induced transcriptional changes to remain a ripe area for future study, particularly as single cell RNA-Seq becomes more accessible.…”