Journal
JOURNAL OF CELL BIOLOGY
Volume 165, Issue 3, Pages 335-346Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200403061
Keywords
autophagy; calcium dysregulation; neurodegenerative diseases
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Funding
- NIA NIH HHS [P01 AG009215, AG09215, AG11542, P01 AG011542] Funding Source: Medline
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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 PSI 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.
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