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Induction of De Novo Α-Synuclein Fibrillization in a Neuronal Model for Parkinson's Disease

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Induction of De Novo Α-Synuclein Fibrillization in a Neuronal Model for Parkinson's Disease Induction of de novo α-synuclein fibrillization in a neuronal model for Parkinson’s disease Mohamed-Bilal Faresa, Bohumil Macoa, Abid Oueslatia,1, Edward Rockensteinb, Natalia Ninkinac, Vladimir L. Buchmanc, Eliezer Masliahb, and Hilal A. Lashuela,d,2 aBrain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, CH-1015, Switzerland; bDepartment of Neurosciences, University of California San Diego, La Jolla, CA 92093; cSchool of Biosciences, Cardiff University, Cardiff, CF10 3AX, United Kingdom; and dQatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, 5825, Qatar Edited by Thomas C. Südhof, Stanford University School of Medicine, Stanford, CA, and approved January 4, 2016 (received for review July 25, 2015) Lewy bodies (LBs) are intraneuronal inclusions consisting primarily periments in mice supported this suggestion, as hα-Syn transgenic of fibrillized human α-synuclein (hα-Syn) protein, which represent (Tg) mice lacking endogenous mouse α-Syn (mα-Syn) expression the major pathological hallmark of Parkinson’s disease (PD). Al- exhibited exacerbated pathology compared with WT counterparts though doubling hα-Syn expression provokes LB pathology in humans, (5), and manifested fibrillar/granular accumulations in the olfac- hα-Syn overexpression does not trigger the formation of fibrillar tory bulb (6). Interestingly, in vitro test-tube experiments also LB-like inclusions in mice. We hypothesized that interactions between showed that small amounts of mα-Syn directly inhibit the fibrilli- exogenous hα-Syn and endogenous mouse synuclein homologs could zation of purified hα-Syn protein in solution (7). be attenuating hα-Syn fibrillization in mice, and therefore, we system- Despite these interesting observations, it remained unclear atically assessed hα-Syn aggregation propensity in neurons derived whether endogenously expressed synuclein homologs directly from α-Syn–KO, β-Syn–KO, γ-Syn–KO, and triple-KO mice lacking ex- inhibit hα-Syn aggregation in neurons, and whether ectopic pression of all three synuclein homologs. Herein, we show that hα-Syn hα-Syn expression in their absence would allow de novo hα-Syn forms hyperphosphorylated (at S129) and ubiquitin-positive LB-like in- fibrillization events. Therefore, we systematically evaluated the clusions in primary neurons of α-Syn–KO, β-Syn–KO, and triple-KO propensity of hα-Syn to aggregate on synuclein-KO backgrounds. mice,aswellasintransgenicα-Syn–KO mouse brains in vivo. Impor- Using a battery of biochemical and imaging techniques, we dem- tantly, correlative light and electron microscopy, immunogold labeling, onstrate that in cultured primary neurons and brains of mα-Syn– and thioflavin-S binding established their fibrillar ultrastructure, and KO mice, overexpressed hα-Syn aggregates readily into inclusions fluorescence recovery after photobleaching/photoconversion experi- that are similar to LBs in terms of solubility, immunoreactivity, and ments showed that these inclusions grow in size and incorporate amyloidogenicity, and represent a bona fide fibrillization process as soluble proteins. We further investigated whether the presence of revealed by serial-section transmission electron microscopy (ssTEM), α homologous -Syn species would interfere with the seeding and live imaging, and response to pharmacological aggregation inhibitors. α − − spreading of -Syn pathology. Our results are in line with increasing Similarly, primary neurons lacking expression of β-Syn (β-Syn / )or α evidence demonstrating that the spreading of -Syn pathology is most of all three homologs (α-, β-, and γ-Syn) also manifest enhanced hα- prominent when the injected preformed fibrils and host-expressed α Syn aggregation, thereby suggesting that endogenous synuclein -Syn monomers are from the same species. These findings provide homologs may represent natural regulators of abnormal α-Syn ag- insights that will help advance the development of neuronal and α gregation. To dissect potential mechanisms underlying this phe- in vivo models for understanding mechanisms underlying h -Syn nomenon, we performed immunoprecipitation and surface plasmon intraneuronal fibrillization and its contribution to PD pathogenesis, and for screening pharmacologic and genetic modulators of α-Syn fibrillization in neurons. Significance Parkinson’s disease | alpha-synuclein | aggregation Although it has been established for over 100 years that Lewy bodies (LBs) represent the major pathological hallmark of Parkin- son’s disease (PD), we still do not know why these fibrillar intra- he aggregation of proteins into fibrillar structures is a key neuronal inclusions of α-synuclein (α-Syn) protein form, or how hallmark of many neurodegenerative disorders. In Parkin- T they contribute to disease progression. One of the major causes son’s disease (PD), α-synuclein (α-Syn), a predominantly pre- underlying this gap in knowledge is the lack of animal models that synaptic protein involved in the regulation of neurotransmitter reproduce the formation of fibrillar LB-like inclusions. In this study, release, abnormally fibrilizes and forms intraneuronal inclusions we show that the absence of human α-Syn (hα-Syn) fibrillization termed “Lewy bodies” (LBs) (1, 2). So far, the mechanisms un- into LBs in mice can be attributed to interactions between hα-Syn derlying LB formation remain poorly understood, and the impact and its endogenously expressed mouse α-Syn homologue. More- of LB presence on neuronal viability remains controversial, in over, we provide well-characterizedprimaryneuronalandinvivo part due to the lack of animal models recapitulating α-Syn models that recapitulate the main molecular feature of PD, bona fibrillization into LB-like inclusions in the brain. fide α-Syn fibrillization. Because patients with familial history of parkinsonism were found carrying either multiplications or point mutations of the Author contributions: M.-B.F., B.M., A.O., E.R., E.M., and H.A.L. designed research; M.-B.F., α-Syn gene SNCA (2), most animal models of PD have been B.M.,A.O.,andE.R.performedresearch;E.R.,N.N.,V.L.B.,andE.M.contributednew generated by overexpressing WT human α-Syn (hα-Syn) or mu- reagents/analytic tools; M.-B.F., B.M., A.O., E.R., N.N., V.L.B., E.M., and H.A.L. analyzed tant forms linked to familial PD (3). Strikingly, although rodent data; and M.-B.F., N.N., V.L.B., and H.A.L. wrote the paper. models expressing hα-Syn do not recapitulate the formation of The authors declare no conflict of interest. fibrillar LBs within dopaminergic neurons, hα-Syn overexpression This article is a PNAS Direct Submission. Drosophila 1Present address: Centre de Recherche du Centre Hospitalier de Québec, Axe Neurosci- in led to dramatic neuronal loss accompanied with ’ α Drosophila ence et Département de Médecine Moléculaire de l Université Laval, Québec, Canada LB-like structures comprising fibrillar -Syn (4). , un- G1V 4G2. α like rodents, do not express an endogenous -Syn homolog, 2To whom correspondence should be addressed. Email: [email protected]. α implying that h -Syn fibril formation could be more favorable This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. in models lacking endogenous α-Syn expression. Subsequent ex- 1073/pnas.1512876113/-/DCSupplemental. E912–E921 | PNAS | Published online February 2, 2016 www.pnas.org/cgi/doi/10.1073/pnas.1512876113 Downloaded by guest on September 30, 2021 resonance (SPR) experiments, which showed that mα-Syn interacts nuclear and cytoplasmic membranes (Fig. 1A and Movie S1). A PNAS PLUS preferentially with aggregated hα-Syn preformed fibrils (PFFs) similar phenotype was observed in primary neurons derived from − − tm1Rosl rather than with monomers. Importantly, in vitro aggregation another SNCA / mouse strain (B6,129 × 1-Snca /J) generated experiments and in vivo assessment of cross-seeding pro- by targeted deletion of two exons of the mα-Syn gene (Fig. S1 C pensities of hα-Syn and mα-Syn showed that the observed cross- and D) (13), thereby establishing that the formation of inclusions species interactions attenuate seeding and spreading of aggre- is directly linked to the specific loss of mα-Syn expression. In line − − gates. These findings possibly explain why current rodent PD with this finding, re-expression of mα-Syn in SNCA / neurons α α models expressing h -Syn do not exhibit pronounced h -Syn significantly reduced the formation of intraneuronal hα-Syn in- fibrillization, and provide models that reproduce a critical clusions, and restored the diffuse distribution of hα-Syn in most pathological feature of the disease: the de novo formation of B α neurons (Fig. 1 ). fibrillar h -Syn aggregates. To investigate whether the total abolishment of mα-Syn ex- α Results pression is necessary to promote h -Syn inclusion formation, we − − assessed whether decreasing mα-Syn levels in WT neurons via Induction of hα-Syn Inclusion Formation in SNCA / Primary Neurons. Several studies have reported that overexpressed hα-Syn in shRNA-mediated silencing is sufficient to promote this process. mouse primary neurons exhibits diffuse localization without forming Transient expression of three different vectors encoding shRNA α discreet inclusions (8–11). To assess whether the absence of mα-Syn hairpin loops showed efficient silencing of m -Syn in transfected would affect this distribution, we examined the localization of neurons as compared to neurons transfected with scrambled transiently expressed hα-Syn in primary neurons derived from
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