Hallacli E, Kayatekin C, Nazeen S, Wang XH, Sheinkopf Z, Sathyakumar S, Sarkar S, Jiang X, Dong X, Di Maio R, Wang W, Keeney MT, Felsky D, Sandoe J, Vahdatshoar A, Udeshi ND, Mani DR, Carr SA, Lindquist S, De Jager PL, Bartel DP, Myers CL, Greenamyre JT, Feany MB, Sunyaev SR, Chung CY, Khurana V. The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability. Cell. 2022 Jun 9;185(12):2035-2056.e33. PubMed.

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  1. In their study, Hallacli and colleagues reveal a completely new physiological function for α-syn, i.e., the regulation of mRNA degradation via direct modulation of Edc4, a protein important for P-body function. To show this, they use a variety of systems, from yeast to human patients, and unbiased screening methods complemented by hypothesis-driven mechanistic experiments.

    While this function has not been reported previously, and it seems puzzling how it could have been overlooked, the evidence presented here is quite convincing, and the observations actually fit well in the current literature. 

    For me personally, the specificity of the P-body modulation to the N-terminus of α-syn and the successive mutual exclusivity of α-syn interaction with P-bodies and membranes is the most interesting part of this story. Our and other labs have found that increased interaction of α-syn with lipids seems to correlate better with disease state in human patient samples, and exerts stronger toxicity in cell and mouse models, than amyloid fibril formation in those same systems.

    How aberrant membrane interaction causes toxicity has been somewhat unclear since it seemed to be exerted by physiologic α-syn and not pathological oligomers, but the assumption was that it just interferes with vesicle trafficking, based on work by Susan Lindquist in the early 2000s. The study here would imply that aberrant lipid binding does not necessarily cause dysfunction via the membrane, but by preventing proper α-syn-P-body interaction as shown here by the experiments in cell culture using the “3K” mutant of α-syn. 

    If the findings hold up to be disease-relevant, there will be a plethora of new exploratory studies into the outcome of impaired P-body modulation, starting a completely new field of α-syn biology with the potential to answer some longstanding questions in the field, e.g., brain region specificity or selective neuronal vulnerability based on the respective local RNA stabilization by synuclein dysfunction.

    On the flip side, way more research in this direction is needed to evaluate the therapeutic potential of this finding, since the current study does not go deeper in that direction. Also unclear is how this relates to amyloid aggregation of α-syn, since the results in this regard are still early days. The correlation of Lewy bodies with mRNA accumulation in human tissue, and the experiments in cell culture with PFF seeding presented here, imply that α-syn aggregates lead to increased mRNA stability, but as said, more research is needed.

    In any case, I think this paper will be a seminal publication in the field.

    View all comments by Tim Bartels

  2. I read this paper with great interest. It raises many exciting questions, both on the physiological function and pathological roles of α-synuclein, for instance, why only α-synuclein and not other family members bind P-bodies when the N-terminal region is pretty conserved? Also, what determines the switch between binding membranes versus P-bodies?

    The authors nicely show that mRNA stability is altered in human neurons, but it remains to be seen if P-body modulation is contributing to these effects. The easiest way is to test this in SNCA knockout human neurons.

    More remains to be done before we can begin to think about therapeutic implications.

    View all comments by Sreeganga Chandra

  3. This article by Hallacli et al. from the Khurana lab opens up new avenues for the biology and pathophysiology of α-synuclein. The work shows that α-synuclein binds to P-body elements and promotes formation of micro-P-bodies in a dose-dependent manner, while pathological α-synuclein isoforms as well as aggregated α-synuclein can inhibit formation of macro-P-bodies. The authors do a good job of linking this biological pathway to Parkinson genetics and showing the biology in iPSC-differentiated neurons from subjects with varying dosages of α-synuclein, and showing that this modulates RNA catabolism.

    In this context, this opens up fascinating new biology for α-synuclein. My group had looked at the relationship between α-synuclein and stress granules years ago (in collaboration with the late John Trojanowski), but never saw anything convincing. Hallacli’s work perhaps now explains why, but also shows an intriguing interaction with RNA metabolism paralleling that seen with RNA-binding proteins linked to ALS as well as for MAPT. Thus, this work extends the emerging link between RNA metabolism and neurodegenerative disease.

    I echo the comments of Tim Bartels. His work had pushed a hypothesis that α-synuclein formed a complex that is associated with lipid membranes, but disruption of the complex leads to cytoplasmic α-synuclein, which could be toxic. They focused on brain and red blood cells and did not examine physiological pathways such as RNA metabolism, but I am struck by the way in which Bartels and Hallacli’s stories both posit an equilibrium between membrane-bound and cytoplasmic α-synuclein.

    The stories differ in the biological outcomes examined. Bartels’ group, with Dennis Selkoe, focused mainly on aggregation, while Hallacli’s work focuses on a physiological outcome, which can impact on pathophysiology when α-synuclein aggregates are present. Nevertheless, both stories point to a biological equilibrium between membrane-bound and membrane-free α-synuclein, which therefore opens the way toward future studies examining the regulation of this equilibrium and these interactions.

    View all comments by Benjamin Wolozin

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  1. New Role for α-Synuclein: Stabilizing mRNA in P-Bodies