PMID:15123735

Citation	Wilson, CA, Murphy, DD, Giasson, BI, Zhang, B, Trojanowski, JQ and Lee, VM (2004) Degradative organelles containing mislocalized alpha-and beta-synuclein proliferate in presenilin-1 null neurons. J. Cell Biol. 165:335-46
Abstract	Presenilin-1 null mutation (PS1 -/-) in mice is associated with morphological alterations and defects in cleavage of transmembrane proteins. Here, we demonstrate that PS1 deficiency also leads to the formation of degradative vacuoles and to the aberrant translocation of presynaptic alpha- and beta-synuclein proteins to these organelles in the perikarya of primary neurons, concomitant with significant increases in the levels of both synucleins. Stimulation of autophagy in control neurons produced a similar mislocalization of synucleins as genetic ablation of PS1. These effects were not the result of the loss of PS1 gamma-secretase activity; however, dysregulation of calcium channels in PS1 -/- cells may be involved. Finally, colocalization of alpha-synuclein and degradative organelles was observed in brains from patients with the Lewy body variant of AD. Thus, aberrant accumulation of alpha- and beta-synuclein in degradative organelles are novel features of PS1 -/- neurons, and similar events may promote the formation of alpha-synuclein inclusions associated with neurodegenerative diseases.
Links	PubMed PMC2172178 Online version:10.1083/jcb.200403061
Keywords	Aged; Aged, 80 and over; Amyloid Precursor Protein Secretases; Animals; Antigens, CD/metabolism; Aspartic Acid Endopeptidases; Autophagy/genetics; Brain/metabolism; Brain/pathology; Brain/physiopathology; Calcium Channels/genetics; Calcium Channels/metabolism; Cells, Cultured; Endopeptidases/metabolism; Female; Humans; Inclusion Bodies/genetics; Inclusion Bodies/metabolism; Lysosome-Associated Membrane Glycoproteins; Lysosomes/metabolism; Lysosomes/pathology; Lysosomes/ultrastructure; Male; Membrane Proteins/genetics; Membrane Proteins/metabolism; Membrane Proteins/physiology; Mice; Mice, Knockout; Microscopy, Electron; Middle Aged; Mutation/genetics; Nerve Tissue Proteins/metabolism; Neurodegenerative Diseases/genetics; Neurodegenerative Diseases/metabolism; Neurodegenerative Diseases/pathology; Neurons/metabolism; Neurons/pathology; Presenilin-1; Protein Transport/genetics; Synucleins; Up-Regulation/genetics; Vacuoles/metabolism; Vacuoles/pathology; alpha-Synuclein; beta-Synuclein
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