The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability

Hallacli, Erinc; Kayatekin, Can; Nazeen, Sumaiya; Wang, Xiou H.; Sheinkopf, Zoe; Sathyakumar, Shubhangi; Sarkar, Satyapriya; Jiang, Xin; Dong, Xianjun; Maio, Roberto Di; Wang, Wen; Keeney, Matthew T.; Felsky, Daniel; Sandoe, Jackson; Vahdatshoar, Aazam; Udeshi, Namrata D.; Mani, D. R.; Carr, Steven A.; Lindquist, Susan; Jager, Philip L. De; Bartel, David P.; Myers, Chad L.; Greenamyre, J. Timothy; Feany, Mel Β.; Sunyaev, Shamil; Chung, Chee Yeun; Khurana, Vikram

doi:10.1016/j.cell.2022.05.008

Cited by 93 publications

(90 citation statements)

References 139 publications

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“…Furthermore, it remains possible that oligomeric complexes may vary in composition. Indeed, mutations in α-synuclein oligomers result in abnormal interactions with RNA binding proteins and mitochondrial proteins, ultimately compromising the molecular machinery and leading to neurodegeneration. , Thus, the cellular functions of PACS-2 E209K in complex with different proteins could potentially be disrupted, analogous to α-synuclein mutants. To this end, PACS-2 E209K was already shown to favorably interact with histone modulators such as SIRT1 and HDAC1 along with the ion channel protein TRPV1 …”

Section: Resultsmentioning

confidence: 99%

The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis

2022

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Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional cytosolic membrane trafficking protein with distinct roles in maintaining cellular homeostasis. Recent clinical reports have described 28 individuals possessing a de novo PACS-2 E209K mutation that present with epileptic seizures and cerebellar dysgenesis. As the PACS-2 E209K missense mutation has become a marker for neurodevelopmental disorders, we sought to characterize its biochemical properties. Accordingly, we observed that the PACS-2 E209K protein exhibited a slower turnover rate relative to PACS-2 wild type (WT) upon cycloheximide treatment in 293T cells. The longer half-life of PACS-2 E209K suggests a disruption in its proteostasis, with the potential for altered protein–protein interactions. Indeed, a regulatory protein in neurodevelopment known as 14-3-3ε was identified as having an increased association with PACS-2 E209K. Subsequently, when comparing the effect of PACS-2 WT and E209K expression on the staurosporine-induced apoptosis response, we found that PACS-2 E209K increased susceptibility to staurosporine-induced apoptosis in HCT 116 cells. Overall, our findings suggest PACS-2 E209K alters PACS-2 proteostasis and favors complex formation with 14-3-3ε, leading to increased cell death in the presence of environmental stressors.

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Section: Resultsmentioning

confidence: 99%

The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis

2022

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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%

“…aS has also been shown to undergo liquid-liquid phase separation and liquid-to-solid phase transition both in vitro 43 and in vivo 44 . It has been identified to be part of functional molecular condensates of the synaptic vesicle protein machinery 45 , processing bodies 46 and assemblies with protein tau 47 . Tau and aS have long been linked as "partners in pathology", with several studies showing the cross-seeding of aggregation [48][49][50] .…”

Section: Introductionmentioning

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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“…Since Hsp31 paralogs are multi-stress responding proteins with new emerging functions, detailed investigations may further decipher the mechanistic insights on how they provide genome protection. Moreover, Hsp31 paralogs also translocate into stress bodies and P-granules, which are recently associated with neurodegenerative diseases (Dudman & Qi, 2020; Hallacli et al, 2022; Miller-Fleming et al, 2014). Therefore, it is critical to characterize the significance of their translocation as it would unravel a broader understanding of DJ-1 family members, specifically in hDJ-1, whose loss of function leads to familial PD.…”

Section: Discussionmentioning

confidence: 99%

Saccharomyces cerevisiae DJ-1 paralogs maintain genome integrity through glycation repair of nucleic acids and proteins

Susarla

Kataria

Kundu

et al. 2022

Preprint

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Reactive carbonyl species (RCS) such as methylglyoxal and glyoxal are potent glycolytic intermediates that extensively damage cellular biomolecules leading to genetic aberration and protein misfolding. Hence, RCS levels are crucial indicators in the progression of various pathological diseases. Besides the glyoxalase system, emerging studies report highly conserved DJ-1/ThiJ/PfpI superfamily proteins as critical regulators of RCS. DJ-1 superfamily proteins, including the human DJ-1, a genetic determinant of Parkinson's disease possess diverse physiological functions paramount for combating multiple stressors. Although S. cerevisiae retains four DJ-1 orthologs (namely Hsp31, Hsp32, Hsp33, and Hsp34), their physiological relevance and collective requirement are still obscure due to their close sequence similarity. Here, we report for the first time that the yeast DJ-1 orthologs function as novel enzymes involved in the preferential scavenge of glyoxal and methylglyoxal, toxic metabolites, and genotoxic agents. At the cellular level, their collective loss induces chronic glycation of the proteome, and nucleic acids, resulting in a spectrum of genetic mutations and reduced mRNA translational efficiency. Furthermore, the Hsp31 paralogs efficiently repair severely glycated macromolecules derived from carbonyl modifications. They also participate in genome maintenance as their absence upregulates DNA damage response pathways when exposed to different genotoxins. Interestingly, yeast DJ-1 orthologs provide robust organellar protection by redistributing into mitochondria to alleviate the glycation damage of mitochondrial DNA and proteins. Taken together, our study uncovers the existence of a novel glycation repair pathway in S. cerevisiae and a possible neuroprotective mechanism of how hDJ-1 confers mitochondrial health during carbonyl stress.

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The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability

Cited by 93 publications

References 139 publications

The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis

The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis

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

Saccharomyces cerevisiae DJ-1 paralogs maintain genome integrity through glycation repair of nucleic acids and proteins

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