Abstract
Proper transport of the Parkinson’s disease (PD) protein, α-synuclein (α-syn), is thought to be crucial for its localization and function at the synapse. Previous work has shown that defects in long distance transport within narrow caliber axons occur early in PD, but how such defects contribute to PD is unknown. Here we test the hypothesis that the NAC region is involved in facilitating proper transport of α-syn within axons via its association with membranes. Excess α-syn or fPD mutant α-synA53T accumulates within larval axons perturbing the transport of synaptic proteins. These α-syn expressing larvae also show synaptic morphological and larval locomotion defects, which correlate with the extent of α-syn-mediated axonal accumulations. Strikingly, deletion of the NAC region (α-synΔ71–82) prevented α-syn accumulations and axonal blockages, and reduced its synaptic localization due to decreased axonal entry and axonal transport of α-syn, due to less α-syn bound to membranes. Intriguingly, co-expression α-synΔ71–82 with full-length α-syn rescued α-syn accumulations and synaptic morphological defects, and decreased the ratio of the insoluble higher molecular weight (HMW)/soluble low molecular weight (LMW) α-syn, indicating that this region is perhaps important for the dimerization of α-syn on membranes. Together, our observations suggest that under physiological conditions, α-syn associates with membranes via the NAC region, and that too much α-syn perturbs axonal transport via aggregate formation, instigating synaptic and behavioral defects seen in PD.
Highlights
Parkinson’s disease (PD) is a common neurodegenerative disease characterized by loss of dopaminergic (DA) neurons in the substanita nigra pars compacta (SNpc) (Dawson and Dawson, 2003; Hardy et al, 2009)
To test the prediction that excess α-syn causes α-syn accumulations within axons which disrupt the transport of essential synaptic proteins to synapses, we utilized a simple genetic model system where the physiological properties of α-syn can be investigated without the expression of endogenous α-syn
SDS-page and Western blot analysis revealed the extent of α-syn protein expression in larval brains, and confirmed that α-synLP3 had an increased level of α-syn expression compared to α-synWT and α-synA53T (Supplementary Figures S1A,B, p < 0.01)
Summary
Parkinson’s disease (PD) is a common neurodegenerative disease characterized by loss of dopaminergic (DA) neurons in the substanita nigra pars compacta (SNpc) (Dawson and Dawson, 2003; Hardy et al, 2009). Α-Syn is a small acidic protein composed of 140 amino acid residues (Ueda et al, 1993) It is a soluble, natively unfolded protein, which likely becomes structured upon binding to phospholipid vesicles (Davidson et al, 1998; Eliezer et al, 2001; Li et al, 2001). The α-syn protein contains three distinct domains; α-Synuclein NAC During Axonal Transport. A highly conserved amino terminal amphipathic α-helical domain, which is thought to associate with membranes (Ueda et al, 1993), a central hydrophobic region known as the nonamyloidal component (NAC) which is proposed to be essential for α-syn aggregation, and an acidic carboxyl-terminal domain, which is suggested to have chaperone-like activity (Ueda et al, 1993; Giasson et al, 2001). While associations between α-syn and molecular motors kinesin-1 and dynein have been shown (Utton et al, 2005), how defects in the axonal transport of α-syn contribute to PD pathology is unclear
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