Open AccessInclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein
Author(s) -
Paula Desplats,
He Jin Lee,
Eun-Jin Bae,
Christina Patrick,
Edward Rockenstein,
Leslie Crews,
Brian Spencer,
Eliezer Masliah,
SeungJae Lee
Publication year - 2009
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0903691106
Subject(s) - lewy body , neuron , biology , alpha synuclein , parkinson's disease , neuroscience , programmed cell death , neurodegeneration , pathology , microbiology and biotechnology , synuclein , apoptosis , disease , medicine , biochemistry
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.