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Preformed fibrils generated from mouse alpha-synuclein produce more inclusion pathology in rats than fibrils generated from rat alpha-synuclein

      Highlights

      • Rat PFFs produce little to no pathology in regions other than the substantia nigra.
      • Mouse PFFs produce significantly more nigral pathology than rat PFFs in a rat model.
      • Alpha-synuclein amino acid sequence impacts efficient inclusion seeding.

      Abstract

      Background

      Alpha-synuclein (α-syn) preformed fibril (PFF)-induced pathology can be used to study the features and progression of synucleinopathies, such as Parkinson's disease. Intrastriatal injection of mouse α-syn PFFs produce accumulation of α-syn pathology in both mice and rats. Previous studies in mice have revealed that greater sequence homology between the α-syn amino acid sequence used to produce PFFs with that of the endogenous host α-syn increases α-syn pathology in vivo.

      New methods

      Based on the prediction that greater sequence homology will result in more α-syn pathology, PFFs generated from recombinant rat α-syn (rPFFs) were used instead of PFFs produced from recombinant mouse α-syn (mPFFs), which are normally used in the model. Rats received unilateral intrastriatal injections of either rPFFs or mPFFs and accumulation of α-syn phosphorylated at serine 129 (pSyn) was examined at 1-month post-surgery.

      Results

      Rats injected with mPFFs exhibited abundant accumulation of α-syn inclusions in the substantia nigra and cortical regions, whereas in rats injected with rPFFs had significantly fewer SNpc neurons containing pSyn inclusions (≈60% fewer) and little, if any, pSyn inclusions were observed in the cortex.

      Conclusions

      Our results suggest that additional factors beyond the degree of sequence homology between host α-syn and injected recombinant α-syn impact efficiency of seeding and subsequent inclusion formation. More practically, these findings caution against the use of rPFFs in the rat preformed fibril model.

      Keywords

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      References

        • Graybiel A.M.
        • Hirsch E.C.
        • Agid Y.
        The nigrostriatal system in Parkinson's disease.
        Adv. Neurol. 1990; 53: 17-29
        • Pollanen M.S.
        • Dickson D.W.
        • Bergeron C.
        Pathology and biology of the Lewy body.
        J. Neuropathol. Exp. Neurol. 1993; 52: 183-191
        • Spillantini M.G.
        • Schmidt M.L.
        • Lee V.M.
        • Trojanowski J.Q.
        • Jakes R.
        • Goedert M.
        Alpha-synuclein in lewy bodies.
        Nature. 1997; 388: 839-840
        • Volpicelli-Daley L.A.
        • Kirik D.
        • Stoyka L.E.
        • Standaert D.G.
        • Harms A.S.
        How can rAAV-alpha-synuclein and the fibril alpha-synuclein models advance our understanding of Parkinson's disease?.
        J. Neurochem. 2016; 139: 131-155
        • Duffy M.F.
        • Collier T.J.
        • Patterson J.R.
        • Kemp C.J.
        • Luke Fischer D.
        • Stoll A.C.
        • Sortwell C.E.
        Quality over quantity: advantages of using alpha-synuclein preformed fibril triggered synucleinopathy to model idiopathic Parkinson's disease.
        Front. Neurosci. 2018; 12: 621
        • Potashkin J.A.
        • Blume S.R.
        • Runkle N.K.
        Limitations of animal models of Parkinson's disease.
        Parkinson's Dis. 2010; (2011): 658083
        • Munoz P.
        • Paris I.
        • Segura-Aguilar J.
        Corrigendum: commentary: evaluation of models of Parkinson's disease.
        Front. Neurosci. 2016; 10: 320
        • Zeiss C.J.
        • Allore H.G.
        • Beck A.P.
        Established patterns of animal study design undermine translation of disease-modifying therapies for Parkinson's disease.
        PloS one. 2017; 12e0171790
        • Volpicelli-Daley L.A.
        • Luk K.C.
        • Patel T.P.
        • Tanik S.A.
        • Riddle D.M.
        • Stieber A.
        • Meaney D.F.
        • Trojanowski J.Q.
        • Lee V.M.
        Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death.
        Neuron. 2011; 72: 57-71
        • Luk K.C.
        • Kehm V.
        • Carroll J.
        • Zhang B.
        • O'Brien P.
        • Trojanowski J.Q.
        • Lee V.M.
        Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice.
        Science. 2012; 338: 949-953
        • Volpicelli-Daley L.A.
        • Luk K.C.
        • Lee V.M.
        Addition of exogenous alpha-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous alpha-synuclein to Lewy body and Lewy neurite-like aggregates.
        Nat. Protoc. 2014; 9: 2135-2146
        • Osterberg V.R.
        • Spinelli K.J.
        • Weston L.J.
        • Luk K.C.
        • Woltjer R.L.
        • Unni V.K.
        Progressive aggregation of alpha-synuclein and selective degeneration of lewy inclusion-bearing neurons in a mouse model of parkinsonism.
        Cell Rep. 2015; 10: 1252-1260
        • Paumier K.L.
        • Luk K.C.
        • Manfredsson F.P.
        • Kanaan N.M.
        • Lipton J.W.
        • Collier T.J.
        • Steece-Collier K.
        • Kemp C.J.
        • Celano S.
        • Schulz E.
        • Sandoval I.M.
        • Fleming S.
        • Dirr E.
        • Polinski N.K.
        • Trojanowski J.Q.
        • Lee V.M.
        • Sortwell C.E.
        Intrastriatal injection of pre-formed mouse alpha-synuclein fibrils into rats triggers alpha-synuclein pathology and bilateral nigrostriatal degeneration.
        Neurobiol. Dis. 2015; 82: 185-199
        • Duffy M.F.
        • Collier T.J.
        • Patterson J.R.
        • Kemp C.J.
        • Luk K.C.
        • Tansey M.G.
        • Paumier K.L.
        • Kanaan N.M.
        • Fischer D.L.
        • Polinski N.K.
        • Barth O.L.
        • Howe J.W.
        • Vaikath N.N.
        • Majbour N.K.
        • El-Agnaf O.M.A.
        • Sortwell C.E.
        Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration.
        J. Neuroinflammation. 2018; 15: 129
        • Patterson J.R.
        • Duffy M.F.
        • Kemp C.J.
        • Howe J.W.
        • Collier T.J.
        • Stoll A.C.
        • Miller K.M.
        • Patel P.
        • Levine N.
        • Moore D.J.
        • Luk K.C.
        • Fleming S.M.
        • Kanaan N.M.
        • Paumier K.L.
        • El-Agnaf O.M.A.
        • Sortwell C.E.
        Time course and magnitude of alpha-synuclein inclusion formation and nigrostriatal degeneration in the rat model of synucleinopathy triggered by intrastriatal alpha-synuclein preformed fibrils.
        Neurobiol. Dis. 2019; 130: 104525
        • Patterson J.R.
        • Polinski N.K.
        • Duffy M.F.
        • Kemp C.J.
        • Luk K.C.
        • Volpicelli-Daley L.A.
        • Kanaan N.M.
        • Sortwell C.E.
        Generation of alpha-synuclein preformed fibrils from monomers and use in vivo.
        JoVE. 2019;
        • Wall N.R.
        • De La Parra M.
        • Callaway E.M.
        • Kreitzer A.C.
        Differential innervation of direct- and indirect-pathway striatal projection neurons.
        Neuron. 2013; 79: 347-360
        • Luk K.C.
        • Covell D.J.
        • Kehm V.M.
        • Zhang B.
        • Song I.Y.
        • Byrne M.D.
        • Pitkin R.M.
        • Decker S.C.
        • Trojanowski J.Q.
        • Lee V.M.
        Molecular and biological compatibility with host alpha-synuclein influences fibril pathogenicity.
        Cell Rep. 2016; 16: 3373-3387
        • Abdelmotilib H.
        • Maltbie T.
        • Delic V.
        • Liu Z.
        • Hu X.
        • Fraser K.B.
        • Moehle M.S.
        • Stoyka L.
        • Anabtawi N.
        • Krendelchtchikova V.
        • Volpicelli-Daley L.A.
        • West A.
        alpha-Synuclein fibril-induced inclusion spread in rats and mice correlates with dopaminergic Neurodegeneration.
        Neurobiol. Dis. 2017; 105: 84-98
        • Shimozawa A.
        • Ono M.
        • Takahara D.
        • Tarutani A.
        • Imura S.
        • Masuda-Suzukake M.
        • Higuchi M.
        • Yanai K.
        • Hisanaga S.I.
        • Hasegawa M.
        Propagation of pathological alpha-synuclein in marmoset brain.
        Acta neuropathologica communications. 2017; 5: 12
        • Chu Y.
        • Muller S.
        • Tavares A.
        • Barret O.
        • Alagille D.
        • Seibyl J.
        • Tamagnan G.
        • Marek K.
        • Luk K.C.
        • Trojanowski J.Q.
        • Lee V.M.Y.
        • Kordower J.H.
        Intrastriatal alpha-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes.
        Brain: J. Neurol. 2019; 142: 3565-3579
        • Lavedan C.
        The synuclein family.
        Genome Res. 1998; 8: 871-880
        • Polinski N.K.
        • Volpicelli-Daley L.A.
        • Sortwell C.E.
        • Luk K.C.
        • Cremades N.
        • Gottler L.M.
        • Froula J.
        • Duffy M.F.
        • Lee V.M.Y.
        • Martinez T.N.
        • Dave K.D.
        Best practices for generating and using alpha-synuclein pre-formed fibrils to model Parkinson's disease in rodents.
        J. Parkinsons Dis. 2018; 8: 303-322
        • Leys C.
        • Ley C.
        • Klein O.
        • Bernard P.
        • Licata L.
        Detecting outliers: do not use standard deviation around the mean, use absolute deviation around the median.
        J. Exp. Soc. Psychol. 2013; 49: 764-766
        • Tarutani A.
        • Suzuki G.
        • Shimozawa A.
        • Nonaka T.
        • Akiyama H.
        • Hisanaga S.
        • Hasegawa M.
        The effect of fragmented pathogenic alpha-synuclein seeds on prion-like propagation.
        J. Biol. Chem. 2016; 291: 18675-18688
        • Grassi D.
        • Howard S.
        • Zhou M.
        • Diaz-Perez N.
        • Urban N.T.
        • Guerrero-Given D.
        • Kamasawa N.
        • Volpicelli-Daley L.A.
        • LoGrasso P.
        • Lasmezas C.I.
        Identification of a highly neurotoxic alpha-synuclein species inducing mitochondrial damage and mitophagy in Parkinson's disease.
        in: Proceedings of the National Academy of Sciences of the United States of America. 115. 2018: E2634-E2643
        • Outeiro T.F.
        • Klucken J.
        • Bercury K.
        • Tetzlaff J.
        • Putcha P.
        • Oliveira L.M.
        • Quintas A.
        • McLean P.J.
        • Hyman B.T.
        Dopamine-induced conformational changes in alpha-synuclein.
        PloS one. 2009; 4e6906
        • Bousset L.
        • Pieri L.
        • Ruiz-Arlandis G.
        • Gath J.
        • Jensen P.H.
        • Habenstein B.
        • Madiona K.
        • Olieric V.
        • Bockmann A.
        • Meier B.H.
        • Melki R.
        Structural and functional characterization of two alpha-synuclein strains.
        Nat. Commun. 2013; 4: 2575
        • Peng C.
        • Gathagan R.J.
        • Covell D.J.
        • Medellin C.
        • Stieber A.
        • Robinson J.L.
        • Zhang B.
        • Pitkin R.M.
        • Olufemi M.F.
        • Luk K.C.
        • Trojanowski J.Q.
        • Lee V.M.
        Cellular milieu imparts distinct pathological alpha-synuclein strains in alpha-synucleinopathies.
        Nature. 2018; 557: 558-563
        • Wang W.
        • Nguyen L.T.
        • Burlak C.
        • Chegini F.
        • Guo F.
        • Chataway T.
        • Ju S.
        • Fisher O.S.
        • Miller D.W.
        • Datta D.
        • Wu F.
        • Wu C.X.
        • Landeru A.
        • Wells J.A.
        • Cookson M.R.
        • Boxer M.B.
        • Thomas C.J.
        • Gai W.P.
        • Ringe D.
        • Petsko G.A.
        • Hoang Q.Q.
        Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein alpha-synuclein.
        in: Proceedings of the National Academy of Sciences of the United States of America. 113. 2016: 9587-9592