Formation of α-synuclein Lewy neurite-like aggregates in axons impedes the transport of distinct endosomes.
Bottom Line: Ultrastructural analyses and live imaging demonstrate that α-syn accumulations do not cause a generalized defect in axonal transport; the inclusions do not fill the axonal cytoplasm, disrupt the microtubule cytoskeleton, or affect the transport of synaptophysin or mitochondria.In addition, the TrkB receptor-associated signaling molecule pERK5 accumulates in α-syn aggregate-bearing neurons.These early effects of α-syn accumulations may predict points of intervention in the neurodegenerative process.
Affiliation: Department of Neurology and Behavioral Neurobiology, University of Alabama, Birmingham, Birmingham, AL 35294 Department of Pathology and Laboratory Medicine, Institute on Aging, and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104 firstname.lastname@example.org.Show MeSH
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Mentions: To determine whether the retrograde transport of other organelles are compromised, we analyzed the movement of TrkB receptors, since these receptors are known to undergo predominantly retrograde axonal transport in endosomes (Deinhardt et al., 2006; Zhou et al., 2012). The most striking change in velocities was found in analysis of retrograde TrkB-GFP transport in brain-derived neurotrophic factor (BDNF)–treated, α-syn inclusion–bearing neurons (Figure 6G and Supplemental Movie S3). Furthermore, the mobility of TrkB-GFP in both the anterograde and retrograde directions also showed significant reductions (Figure 6B), which was reflected by significant increases in the number of pauses (Figure 6D) and reversals (Figure 6E), although the number of particles per 50 μm is unchanged (Figure 6C). In BDNF-treated neurons bearing α-syn inclusions, the velocities of TrkB-GFP showed a significant shift into the lower-velocity bins relative to the control neurons (Figure 6G). In addition, analysis of the median velocities revealed a significant decrease in the neurons exposed to PFFs compared with PBS-treated controls. Images of TrkB-GFP in BDNF-treated neurons with axonal α-syn fibrillar aggregates showed that TrkB-GFP appeared to be localized to more discrete puncta compared with control axons (Figure 6A), possibly reflective of its reduced mobility. The kymographs provide a visual representation of the retrograde movement of TrkB-GFP in BDNF-treated neurons, and it can be seen in both the kymographs and overall quantitation that there were fewer mobile TrkB-GFP particles in neurons exposed to PFFs with α-syn aggregates.
Affiliation: Department of Neurology and Behavioral Neurobiology, University of Alabama, Birmingham, Birmingham, AL 35294 Department of Pathology and Laboratory Medicine, Institute on Aging, and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104 email@example.com.