Experimental studies in flies, mice, and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer's disease (AD). The mechanisms underlying these impairments in axonal transport, however, remain poorly understood. Here we report that the Swedish familial AD mutation causes a standstill of the amyloid precursor protein (APP) in the axons at the expense of its reduced anterograde transport. The standstill reflects the perturbed directionality of the axonal transport of APP, which spends significantly more time traveling in the retrograde direction. This ineffective movement is accompanied by an enhanced association of dynactin-1 with APP, which suggests that reduced anterograde transport of APP is the result of enhanced activation of the retrograde molecular motor dynein by dynactin-1. The impact of the Swedish mutation on axonal transport is not limited to the APP vesicles since it also reverses the directionality of a subset of early endosomes, which become enlarged and aberrantly accumulate in distal locations. In addition, it also reduces the trafficking of lysosomes due to their less effective retrograde movement. Altogether, our experiments suggest a pivotal involvement of retrograde molecular motors and transport in the mechanisms underlying impaired axonal transport in AD and reveal significantly more widespread derangement of axonal transport pathways in the pathogenesis of AD.

• Keywords
• Alzheimer’s disease, amyloid precursor protein, axonal transport, dynactin-1, early endosomes, familial pathogenic variants, lysosomes,
• MeSH
• Alzheimer Disease * metabolism   genetics   pathology   MeSH
• Amyloid beta-Protein Precursor * genetics   metabolism   MeSH
• Axonal Transport * genetics   MeSH
• Axons metabolism   pathology   MeSH
• Dynactin Complex metabolism   genetics   MeSH
• Dyneins metabolism   MeSH
• Endosomes metabolism   genetics   MeSH
• Genetic Variation MeSH
• Humans MeSH
• Lysosomes metabolism   MeSH
• Mutation MeSH
• Mice MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Amyloid beta-Protein Precursor * MeSH
• DCTN1 protein, human MeSH Browser
• Dynactin Complex MeSH
• Dyneins MeSH

The distinctive pathological hallmarks of Parkinson's disease are the progressive death of dopaminergic neurons and the intracellular accumulation of Lewy bodies enriched in α-synuclein protein. Several lines of evidence from the study of sporadic, familial and pharmacologically induced forms of human Parkinson's disease also suggest that mitochondrial dysfunction plays an important role in disease progression. Although many functions have been proposed for α-synuclein, emerging data from human and animal models of Parkinson's disease highlight a role for α-synuclein in the control of neuronal mitochondrial dynamics. Here, we review the α-synuclein structural, biophysical and biochemical properties that influence relevant mitochondrial dynamic processes such as fusion-fission, transport and clearance. Drawing on current evidence, we propose that α-synuclein contributes to the mitochondrial defects that are associated with the pathology of this common and progressive neurodegenerative disease.

• Keywords
• Fusion-fission, Mitochondria, Mitophagy, Parkinson's disease, Synuclein, Transport,
• MeSH
• alpha-Synuclein chemistry   metabolism   MeSH
• Models, Biological MeSH
• Humans MeSH
• Mitochondrial Dynamics * MeSH
• Mitophagy MeSH
• Parkinson Disease metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• alpha-Synuclein MeSH

The etiology of Parkinson's disease (PD) converges on a common pathogenic pathway of mitochondrial defects in which α-Synuclein (αSyn) is thought to play a role. However, the mechanisms by which αSyn and its disease-associated allelic variants cause mitochondrial dysfunction remain unknown. Here, we analyzed mitochondrial axonal transport and morphology in human-derived neurons overexpressing wild-type (WT) αSyn or the mutated variants A30P or A53T, which are known to have differential lipid affinities. A53T αSyn was enriched in mitochondrial fractions, inducing significant mitochondrial transport defects and fragmentation, while milder defects were elicited by WT and A30P. We found that αSyn-mediated mitochondrial fragmentation was linked to expression levels in WT and A53T variants. Targeted delivery of WT and A53T αSyn to the outer mitochondrial membrane further increased fragmentation, whereas A30P did not. Genomic editing to disrupt the N-terminal domain of αSyn, which is important for membrane association, resulted in mitochondrial elongation without changes in fusion-fission protein levels, suggesting that αSyn plays a direct physiological role in mitochondrial size maintenance. Thus, we demonstrate that the association of αSyn with the mitochondria, which is modulated by protein mutation and dosage, influences mitochondrial transport and morphology, highlighting its relevance in a common pathway impaired in PD.

• MeSH
• alpha-Synuclein chemistry   genetics   metabolism   MeSH
• Axonal Transport MeSH
• Homeostasis * MeSH
• Humans MeSH
• Human Embryonic Stem Cells metabolism   MeSH
• Mitochondrial Membranes metabolism   MeSH
• Mitochondria metabolism   MeSH
• Mutant Proteins metabolism   MeSH
• Neurons pathology   MeSH
• Parkinson Disease genetics   pathology   MeSH
• Protein Domains MeSH
• Organelle Size MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• alpha-Synuclein MeSH
• Mutant Proteins MeSH