Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein.
Neuronal accumulation of alpha-synuclein and Lewy body formation are characteristic to many neurodegenerative diseases, including Parkinson's disease (PD). This Lewy pathology appears to spread throughout the brain as the disease progresses. Furthermore, recent studies showed the occurrence of Lewy pathology in neurons grafted into the brains of PD patients, suggesting the spread of pathology from the host tissues to the grafts. The mechanism underlying this propagation is unknown. Here, we show that alpha-synuclein is transmitted via endocytosis to neighboring neurons and neuronal precursor cells, forming Lewy-like inclusions. Moreover, alpha-synuclein was transmitted from the affected neurons to engrafted neuronal precursor cells in a transgenic model of PD-like pathology. Failure of the protein quality control systems, especially lysosomes, promoted the accumulation of transmitted alpha-synuclein and inclusion formation. Cells exposed to neuron-derived alpha-synuclein showed signs of apoptosis, such as nuclear fragmentation and caspase 3 activation, both in vitro and in vivo. These findings demonstrate the cell-to-cell transmission of alpha-synuclein aggregates and provide critical insights into the mechanism of pathological progression in PD and other proteinopathies.
Desplats
Paula
P
Department of Neurosciences and Pathology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Lee
He-Jin
HJ
Bae
Eun-Jin
EJ
Patrick
Christina
C
Rockenstein
Edward
E
Crews
Leslie
L
Spencer
Brian
B
Masliah
Eliezer
E
Lee
Seung-Jae
SJ
D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D002460:Cell Line; D006801:Humans; D016631:Lewy Bodies / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology*; D051381:Rats; D033581:Stem Cell Transplantation; D009435:Synaptic Transmission; D051844:alpha-Synuclein / Q000378:metabolism* / Q000633:toxicity
D051844:alpha-Synuclein