Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies.
Abnormal neuronal aggregation of alpha-synuclein is implicated in the development of many neurological disorders, including Parkinson disease and dementia with Lewy bodies. Glial cells also show extensive alpha-synuclein pathology and may contribute to disease progression. However, the mechanism that produces the glial alpha-synuclein pathology and the interaction between neurons and glia in the disease-inflicted microenvironment remain unknown. Here, we show that alpha-synuclein proteins released from neuronal cells are taken up by astrocytes through endocytosis and form inclusion bodies. The glial accumulation of alpha-synuclein through the transmission of the neuronal protein was also demonstrated in a transgenic mouse model expressing human alpha-synuclein. Furthermore, astrocytes that were exposed to neuronal alpha-synuclein underwent changes in the gene expression profile reflecting an inflammatory response. Induction of pro-inflammatory cytokines and chemokines correlated with the extent of glial accumulation of alpha-synuclein. Together, these results suggest that astroglial alpha-synuclein pathology is produced by direct transmission of neuronal alpha-synuclein aggregates, causing inflammatory responses. This transmission step is thus an important mediator of pathogenic glial responses and could qualify as a new therapeutic target.
Lee
He-Jin
HJ
Department of Anatomy, School of Medicine, Konkuk University, Seoul 143-701, Korea .
Suk
Ji-Eun
JE
Patrick
Christina
C
Bae
Eun-Jin
EJ
Cho
Ji-Hoon
JH
Rho
Sangchul
S
Hwang
Daehee
D
Masliah
Eliezer
E
Lee
Seung-Jae
SJ
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D007249:Inflammation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051844:alpha-Synuclein / Q000378:metabolism*
D017077:Culture Media, Conditioned; D051844:alpha-Synuclein