Transcellular propagation of fibrillar α-synuclein from enteroendocrine to neuronal cells requires cell-to-cell contact and is Rab35-dependent.

Autor: Rodrigues PV; Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), 10000 Giuseppe Maximo Scolfaro St., Campinas, São Paulo, 13083-100, Brazil.; Department of Structural and Functional Biology, State University of Campinas, Campinas, São Paulo, Brazil., de Godoy JVP; Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), 10000 Giuseppe Maximo Scolfaro St., Campinas, São Paulo, 13083-100, Brazil.; Department of Structural and Functional Biology, State University of Campinas, Campinas, São Paulo, Brazil., Bosque BP; Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), 10000 Giuseppe Maximo Scolfaro St., Campinas, São Paulo, 13083-100, Brazil.; Department of Structural and Functional Biology, State University of Campinas, Campinas, São Paulo, Brazil., Amorim Neto DP; Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), 10000 Giuseppe Maximo Scolfaro St., Campinas, São Paulo, 13083-100, Brazil.; Department of Structural and Functional Biology, State University of Campinas, Campinas, São Paulo, Brazil., Tostes K; Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), 10000 Giuseppe Maximo Scolfaro St., Campinas, São Paulo, 13083-100, Brazil., Palameta S; Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), 10000 Giuseppe Maximo Scolfaro St., Campinas, São Paulo, 13083-100, Brazil., Garcia-Rosa S; Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), 10000 Giuseppe Maximo Scolfaro St., Campinas, São Paulo, 13083-100, Brazil., Tonoli CCC; Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), 10000 Giuseppe Maximo Scolfaro St., Campinas, São Paulo, 13083-100, Brazil., de Carvalho HF; Department of Structural and Functional Biology, State University of Campinas, Campinas, São Paulo, Brazil., de Castro Fonseca M; Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), 10000 Giuseppe Maximo Scolfaro St., Campinas, São Paulo, 13083-100, Brazil. mdecastr@caltech.edu.; Department of Structural and Functional Biology, State University of Campinas, Campinas, São Paulo, Brazil. mdecastr@caltech.edu.; Laboratory of Sarkis Mazmanian, Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA, USA. mdecastr@caltech.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2022 Mar 09; Vol. 12 (1), pp. 4168. Date of Electronic Publication: 2022 Mar 09.
DOI: 10.1038/s41598-022-08076-5
Abstrakt: Parkinson's disease (PD) is a neurodegenerative condition featured by motor dysfunction, death of midbrain dopaminergic neurons and accumulation of α-synuclein (αSyn) aggregates. Growing evidence suggests that PD diagnosis happens late in the disease progression and that the pathology may originate much earlier in the enteric nervous system (ENS) before advancing to the brain, via autonomic fibers. It was recently described that a specific cell type from the gut epithelium named enteroendocrine cells (EECs) possess many neuron-like properties including αSyn expression. By facing the gut lumen and being directly connected with αSyn-containing enteric neurons in a synaptic manner, EECs form a neural circuit between the gastrointestinal tract and the ENS, thereby being a possible key player in the outcome of PD in the gut. We have characterized the progression and the cellular mechanisms involved in αSyn pre-formed fibrils (PFFs) transfer from EECs to neuronal cells. We show that brain organoids efficiently internalize αSyn PFF seeds which triggers the formation of larger intracellular inclusions. In addition, in the enteroendocrine cell line STC-1 and in the neuronal cell line SH-SY5Y, αSyn PFFs induced intracellular calcium (Ca 2+ ) oscillations on an extracellular Ca 2+ source-dependent manner and triggered αSyn fibrils internalization by endocytosis. We characterized the spread of αSyn PFFs from enteroendocrine to neuronal cells and showed that this process is dependent on physical cell-to-cell contact and on Rab35 GTPase. Lastly, inhibition of Rab35 increases the clearance of αSyn fibrils by redirecting them to the lysosomal compartment. Therefore, our results reveal mechanisms that contribute to the understanding of how seeded αSyn fibrils promote the progression of αSyn pathology from EECs to neuronal cells shifting the focus of PD etiology to the ENS.
(© 2022. The Author(s).)
Databáze: MEDLINE
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