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Published online 3 May 2004. doi:10.1083/jcb.200403061
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 3, 335-346
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Article

Degradative organelles containing mislocalized {alpha}- and ß-synuclein proliferate in presenilin-1 null neurons



Christina A. Wilson1, Diane D. Murphy1, Benoit I. Giasson1, Bin Zhang1, John Q. Trojanowski1,2, and Virginia M.-Y. Lee1

1 Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA 19104
2 Institute on Aging, University of Pennsylvania, Philadelphia, PA 19104

Address correspondence to Virginia M.-Y. Lee, Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA 19104. Tel.: (215) 662-6427. Fax: (215) 349-5909. email: vmylee{at}mail.med.upenn.edu

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 ß-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 ß-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.

Key Words: autophagy; calcium dysregulation; neurodegenerative diseases

D.D. Murphy's present address is National Institute of Neurological Diseases and Stroke, Neuroscience Center, Room 2228 6001 Executive Blvd., Rockville, MD 20852.

Abbreviations used in this paper: AD, Alzheimer's disease; APP, amyloid precursor protein; DMEM, Dulbecco's minimum essential medium; FAD, familial AD; LBVAD, Lewy body variant of AD; NFL, neurofilament-L; NSE, neuron-specific enolase; PD, Parkinson's disease; PS1, presenilin-1.


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