Conformation-specific Antibodies Targeting Aggregated Forms of α-synuclein Block the Propagation of Synucleinopathy

다국어 초록 (Multilingual Abstract)

Abnormal aggregation of α-synuclein is a key element in the pathogenesis of several neurodegenerative diseases, including Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy. α-synuclein aggregation spreads through various brain regions during the course of disease progression, a propagation that is thought to be mediated by the secretion and subsequent uptake of extracellular α-synuclein aggregates between neuronal cells. Thus, aggregated forms of this protein have emerged as promising targets for disease-modifying therapy for PD and related diseases. Here, we generated and characterized conformation-specific antibodies that preferentially recognize aggregated forms of α-synuclein. These antibodies promoted phagocytosis of extracellular α-synuclein aggregates by microglial cells and interfered with cell-to-cell propagation of α-synuclein. In an α-synuclein transgenic model, passive immunization with aggregate-specific antibodies significantly ameliorated pathological phenotypes, reducing α-synuclein aggregation, gliosis, inflammation, and neuronal loss. These results suggest that conformation-specific antibodies targeting α-synuclein aggregates are promising therapeutic agents for PD and related synucleinopathies.

참고문헌 (Reference)

1 Mehra S, "α-Synuclein misfolding and aggregation: implications in Parkinson's disease pathogenesis" 1867 : 890-908, 2019

2 Tran HT, "Α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration" 7 : 2054-2065, 2014

3 Rey NL, "Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson's disease" 213 : 1759-1778, 2016

4 Schaser AJ, "Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy" 8 : 150-, 2020

5 Katsinelos T, "The role of antibodies and their receptors in protection against ordered protein assembly in neurodegeneration" 10 : 1139-, 2019

6 Cookson MR, "The biochemistry of Parkinson's disease" 74 : 29-52, 2005

7 Zhang B, "Stereotaxic targeting of alphasynuclein pathology in mouse brain using preformed fibrils" 1948 : 45-57, 2019

8 Braak H, "Staging of brain pathology related to sporadic Parkinson's disease" 24 : 197-211, 2003

9 Braak H, "Stages in the development of Parkinson's diseaserelated pathology" 318 : 121-134, 2004

10 Brundin P, "Prying into the prion hypothesis for Parkinson's disease" 37 : 9808-9818, 2017

11 Mougenot AL, "Prion-like acceleration of a synucleinopathy in a transgenic mouse model" 33 : 2225-2228, 2012

12 La Vitola P, "Peripheral inflammation exacerbates α-synuclein toxicity and neuropathology in Parkinson's models" 47 : 43-60, 2021

13 Dauer W, "Parkinson's disease: mechanisms and models" 39 : 889-909, 2003

14 Jang A, "Nonclassical exocytosis of alpha-synuclein is sensitive to folding states and promoted under stress conditions" 113 : 1263-1274, 2010

15 Kim C, "Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia" 4 : 1562-, 2013

16 Flores-Cuadrado A, "Neurodegeneration and contralateral α-synuclein induction after intracerebral α-synuclein injections in the anterior olfactory nucleus of a Parkinson's disease A53T mouse model" 7 : 56-, 2019

17 Mezias C, "Neural connectivity predicts spreading of alpha-synuclein pathology in fibrilinjected mouse models: involvement of retrograde and anterograde axonal propagation" 134 : 104623-, 2020

18 Lee HJ, "Membrane-bound alpha-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form" 277 : 671-678, 2002

19 Hansson O, "Levels of cerebrospinal fluid α-synuclein oligomers are increased in Parkinson's disease with dementia and dementia with Lewy bodies compared to Alzheimer's disease" 6 : 25-, 2014

20 Chen M, "Investigation of alpha-synuclein fibril structure by site-directed spin label"

21 Lee HJ, "Intravesicular localization and exocytosis of alpha-synuclein and its aggregates" 25 : 6016-6024, 2005

22 Paumier KL, "Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration" 82 : 185-199, 2015

23 Chu Y, "Intrastriatal alpha-synuclein fibrils in monkeys : spreading, imaging and neuropathological changes" 142 : 3565-3579, 2019

24 Sacino AN, "Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapidonset motor phenotype in transgenic mice" 111 : 10732-10737, 2014

25 Luk KC, "Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice" 209 : 975-986, 2012

26 Desplats P, "Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein" 106 : 13010-13015, 2009

27 Kim C, "Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation" 13 : 43-, 2018

28 Bae EJ, "Glucocerebrosidase depletion enhances cell-to-cell transmission of α-synuclein" 5 : 4755-, 2014

29 Kim TK, "G9a-mediated regulation of OXT and AVP expression in the basolateral amygdala mediates stress-induced lasting behavioral depression and its reversal by exercise" 53 : 2843-2856, 2016

30 Lee HJ, "Extracellular α--synuclein-a novel and crucial factor in Lewy body diseases" 10 : 92-98, 2014

31 박민정 ; 천상명 ; 배혜란 ; 김상호 ; 김재우, "Elevated Levels of α-Synuclein Oligomer in the Cerebrospinal Fluid of Drug-Naïve Patients with Parkinson’s Disease" 대한신경과학회 7 (7): 215-222, 2011

32 Lee HJ, "Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies" 285 : 9262-9272, 2010

33 Rockenstein E, "Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters" 68 : 568-578, 2002

34 El-Agnaf O, "Differential effects of immunotherapy with antibodies targeting α-synuclein oligomers and fibrils in a transgenic model of synucleinopathy" 104 : 85-96, 2017

35 Paleologou KE, "Detection of elevated levels of soluble alpha-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies" 132 (132): 1093-1101, 2009

36 Tokuda T, "Decreased alpha-synuclein in cerebrospinal fluid of aged individuals and subjects with Parkinson's disease" 349 : 162-166, 2006

37 Lee HJ, "Clearance and deposition of extracellular alpha-synuclein aggregates in microglia" 372 : 423-428, 2008

38 Gustafsson G, "Cellular uptake of α-synuclein oligomer-selective antibodies is enhanced by the extracellular presence of α-synuclein and mediated via Fcγ receptors" 37 : 121-131, 2017

39 Lee SJ, "Cell-to-cell transmission of non-prion protein aggregates" 6 : 702-706, 2010

40 Lee HJ, "Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein" 40 : 1835-1849, 2008

41 Bae EJ, "Antibody-aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission" 32 : 13454-13469, 2012

42 Chesselet MF, "A progressive mouse model of Parkinson's disease: the Thy1-aSyn (“Line 61”) mice" 9 : 297-314, 2012