Ejlerskov P, Hultberg JG, Wang J, Carlsson R, Ambjørn M, Kuss M, Liu Y, Porcu G, Kolkova K, Friis Rundsten C, Ruscher K, Pakkenberg B, Goldmann T, Loreth D, Prinz M, Rubinsztein DC, Issazadeh-Navikas S. Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson's Disease-like Dementia. Cell. 2015 Oct 8;163(2):324-39. PubMed.
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U.K. Dementia Research Institute at University College London
The study by Ejlerskov et al. provides interesting new evidence for the role of Interferon-β (IFNβ) in the earliest events of the disease cascade of synucleinopathies such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). In an attempt to elucidate the role of IFNβ in neurodegeneration, the authors analyze lfnb-/- mice, first testing for cognitive and behavioral deficits and then, upon observing a pronounced motor phenotype and behavioral deficits, determine a major role for the IFNβ/IFNAR pathway in neuronal autophagy.
The study has several important implications. First, the connection between proteins involved in the inflammatory system and neurodegeneration has been of great interest lately, but the common assumption has been that the mechanisms involved center around microglia-mediated clearance of amyloid protein. While the authors do not go into detail about whether this mechanism is contributing here (only glial counts, but not their activation state, were analyzed), they do provide another general cellular pathway, autophagy, that is affected by IFNβ/IFNAR and leads to dysregulation of protein homeostasis. Surprisingly, this dysregulation seems to lead to a motor phenotype and the neuronal aggregation of α-synuclein (αSyn). This is important, because secondly, the work further establishes a link between impaired autophagy, aggregation of αSyn, and early neurodegeneration in PD. Autophagy in general, and mitophagy in particular, have been strongly linked to PD through familial mutations in several genes encoding proteins such as PINK1/Parkin (Ashrafi et al., 2014) and LRRK2 (Schapansky et al., 2014; Orenstein et al., 2013). While αSyn has been shown to be degraded by chaperone-mediated autophagy in an in vitro system (Vogiatzi et al., 2008; Cuervo et al., 2004), the authors demonstrate here elegantly the accumulation of endogenous αSyn in an in vivo system when autophagy is impaired. The work is therefore interesting for a third reason, since it establishes a novel mouse model for PD that recapitulates the aggregation of αSyn in patient brain, without the need for overexpression of the protein itself, revealing pathways that are apparently upstream of amyloid and Lewy body formation. Now it will be important to study these pathways in this model in more detail to investigate whether they are linked not only to pathological changes in αSyn homeostasis but also to functional changes for other genes implicated in PD, as mentioned above.
In terms of changes in αSyn homeostasis, I find it very interesting that the authors report a decrease in physiological tetrameric αSyn, a form that has been found by us (Bartels et al., 2011) and others (Wang et al., 2011), while blockage of autophagy apparently leads to an accumulation of aggregation-prone monomeric αSyn. These changes recapitulate what is seen in SNCA mutation carriers (Dettmer et al., 2015) and therefore could link inherited PD cases to the underlying mechanism of sporadic PD, in which neuronal autophagy is potentially impaired by environmental factors. It is now important to investigate how the autophagy pathway could lead to an apparent shift in the ratio of tetrameric to monomeric αSyn, either through blockage of tetramer assembly pathways or the preferential degradation of one species over the other under these conditions.
Another open question is the specificity of αSyn accumulation versus other amyloidogenic proteins such as Aβ or prion protein that should also be affected by dysfunctional protein homeostasis. One could speculate that autophagosomal degradation is particularly important for αSyn degradation, but further studies are necessary. This study opens up a plethora of new ways to study the pathomechanism in PD and related neurodegenerative diseases and further raises the importance of the autophagic pathway as a target in drug discovery.
References:
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Schapansky J, Nardozzi JD, Felizia F, LaVoie MJ. Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy. Hum Mol Genet. 2014 Aug 15;23(16):4201-14. Epub 2014 Mar 27 PubMed.
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Wang W, Perovic I, Chittuluru J, Kaganovich A, Nguyen LT, Liao J, Auclair JR, Johnson D, Landeru A, Simorellis AK, Ju S, Cookson MR, Asturias FJ, Agar JN, Webb BN, Kang C, Ringe D, Petsko GA, Pochapsky TC, Hoang QQ. A soluble α-synuclein construct forms a dynamic tetramer. Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):17797-802. Epub 2011 Oct 17 PubMed.
Dettmer U, Newman AJ, Soldner F, Luth ES, Kim NC, von Saucken VE, Sanderson JB, Jaenisch R, Bartels T, Selkoe D. Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat Commun. 2015 Jun 16;6:7314. PubMed.
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