Suppression of dynamin GTPase decreases α-synuclein uptake by neuronal and oligodendroglial cells: a potent therapeutic target for synucleinopathy.
BACKGROUND
The intracellular deposition of misfolded proteins is a common neuropathological hallmark of most neurodegenerative disorders. Increasing evidence suggests that these pathogenic proteins may spread to neighboring cells and induce the propagation of neurodegeneration.


RESULTS
In this study, we have demonstrated that α-synuclein (αSYN), a major constituent of intracellular inclusions in synucleinopathies, was taken up by neuronal and oligodendroglial cells in both a time- and concentration-dependent manner. Once incorporated, the extracellular αSYN was immediately assembled into high-molecular-weight oligomers and subsequently formed cytoplasmic inclusion bodies. Furthermore, αSYN uptake by neurons and cells of the oligodendroglial lineage was markedly decreased by the genetic suppression and pharmacological inhibition of the dynamin GTPases, suggesting the involvement of the endocytic pathway in this process.


CONCLUSIONS
Our findings shed light on the mode of αSYN uptake by neuronal and oligodendroglial cells and identify therapeutic strategies aimed at reducing the propagation of protein misfolding.
Division of Neurology, Department of Neuroscience and Sensory Organs, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.
Masatoshi
M
Konno
Takafumi
T
Hasegawa
Toru
T
Baba
Emiko
E
Miura
Naoto
N
Sugeno
Akio
A
Kikuchi
Fabienne C
FC
Fiesel
Tsutomu
T
Sasaki
Masashi
M
Aoki
Yasuto
Y
Itoyama
Atsushi
A
Takeda
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D018920:Coculture Techniques; D034281:Dynamins / Q000037:antagonists & inhibitors*; D004705:Endocytosis; D004791:Enzyme Inhibitors; D005455:Fluorescent Antibody Technique; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018613:Microscopy, Confocal; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism*
D004791:Enzyme Inhibitors; D051844:alpha-Synuclein; D034281:Dynamins