Abstract
Alpha-synuclein is a major protein constituent of Lewy bodies and mutations in alpha-synuclein cause familial autosomal dominant Parkinson's disease. One explanation for the formation of perikaryal and neuritic aggregates of alpha-synuclein, which is a presynaptic protein, is that the mutations disrupt alpha-synuclein transport and lead to its proximal accumulation. We found that mutant forms of alpha-synuclein, either associated with Parkinson's disease (A30P or A53T) or mimicking defined serine, but not tyrosine, phosphorylation states exhibit reduced axonal transport following transfection into cultured neurons. Furthermore, transfection of A30P, but not wild-type, alpha-synuclein results in accumulation of the protein proximal to the cell body. We propose that the reduced axonal transport exhibited by the Parkinson's disease-associated alpha-synuclein mutants examined in this study might contribute to perikaryal accumulation of alpha-synuclein and hence Lewy body formation and neuritic abnormalities in diseased brain.
Highlights
Introduction αSynuclein is a 14 kDa phosphoprotein of 140 amino acids that was first identified as a presynaptic protein in rat brain (Maroteaux et al, 1988)
Two pieces of evidence suggest that α-synuclein has a causal role in neurodegenerative disease: (1) two rare point mutations in α-synuclein (Ala53Thr and Ala30Pro) have been found in a few families with autosomal dominant Parkinson’s disease (Polymeropoulos et al, 1997; Kruger et al, 1998); (2) αsynuclein accumulates in Lewy bodies and other pathological inclusions in conditions including Parkinson’s disease, multiple system atrophy, neurodegeneration with brain iron accumulation and Alzheimer’s disease (Masliah et al, 1996; Spillantini et al, 1997; Lippa et al, 1998; Spillantini et al, 1998; Gai et al, 1998; Irizarry et al, 1998; Braak et al, 1999; Iwanaga et al, 1999; Hamilton, 2000), highlighting its importance in the pathogenesis of these neurodegenerative disorders
By 3.5 hours after transfection, we observed α-synuclein immunoreactivity at the extremities of some individual neurites, at long distances from the cell body, indicating that these accumulations represent α-synuclein that had already reached the terminals and could have done so in this time if they had travelled at a rate equivalent to that of organelles moving in the fast component of axonal transport
Summary
Introduction αSynuclein is a 14 kDa phosphoprotein of 140 amino acids that was first identified as a presynaptic protein in rat brain (Maroteaux et al, 1988). Metabolic labelling of neuronal proteins in the rat optic nerve has shown that most α-synuclein (76%) moves in the slow component of axonal transport (Jensen et al, 1998; Jensen et al, 1999). A proportion of α-synuclein binds to vesicles and is moved in the fast component of axonal transport. It is conceivable that defective α-synuclein transport could lead to less αsynuclein exiting from the cell body along the axon and effectively cause local overexpression of α-synuclein in the perikaryon. Such overexpression might alter the normal cellular localization of α-synuclein and affect its folding and/or association with other proteins, leading to its accumulation as
Sign-in/Register to view highlights & summary 
Paper version not known (
Free)
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call