Parkinson's disease alpha-synuclein mutations exhibit defective axonal transport in cultured neurons.
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.
Saha
Anirban R
AR
Department of Neuroscience, PO Box 38, Institute of Psychiatry, King's College London, De Crespigny Park, London, SE5 8AF, UK.
Hill
Josephine
J
Utton
Michelle A
MA
Asuni
Ayodeji A
AA
Ackerley
Steven
S
Grierson
Andrew J
AJ
Miller
Christopher C
CC
Davies
Alun M
AM
Buchman
Vladimir L
VL
Anderton
Brian H
BH
Hanger
Diane P
DP
D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D001483:Base Sequence; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D017354:Point Mutation; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D051843:Synucleins; D014162:Transfection; D051844:alpha-Synuclein
D018076:DNA, Complementary; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; D012694:Serine