{alpha}-synuclein and its A30P mutant affect actin cytoskeletal structure and dynamics.
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ABSTRACT: The function of alpha-synuclein, a soluble protein abundant in the brain and concentrated at presynaptic terminals, is still undefined. Yet, alpha-synuclein overexpression and the expression of its A30P mutant are associated with familial Parkinson's disease. Working in cell-free conditions, in two cell lines as well as in primary neurons we demonstrate that alpha-synuclein and its A30P mutant have different effects on actin polymerization. Wild-type alpha-synuclein binds actin, slows down its polymerization and accelerates its depolymerization, probably by monomer sequestration; A30P mutant alpha-synuclein increases the rate of actin polymerization and disrupts the cytoskeleton during reassembly of actin filaments. Consequently, in cells expressing mutant alpha-synuclein, cytoskeleton-dependent processes, such as cell migration, are inhibited, while exo- and endocytic traffic is altered. In hippocampal neurons from mice carrying a deletion of the alpha-synuclein gene, electroporation of wild-type alpha-synuclein increases actin instability during remodeling, with growth of lamellipodia-like structures and apparent cell enlargement, whereas A30P alpha-synuclein induces discrete actin-rich foci during cytoskeleton reassembly. In conclusion, alpha-synuclein appears to play a major role in actin cytoskeletal dynamics and various aspects of microfilament function. Actin cytoskeletal disruption induced by the A30P mutant might alter various cellular processes and thereby play a role in the pathogenesis of neurodegeneration.
Project description:Nutritional influences have been discussed as potential modulators of Parkinson’s disease (PD) pathology. In animal models, a high fat diet (HFD) with greater intake of lipid-derived calories leads to accelerated disease onset and progression. The underlying molecular mechanisms of HFD-induced aggravated pathology, however, remain largely unclear. In this study, we aimed to further illuminate the effects of a fat-enriched diet in PD by examining the brainstem and hippocampal transcriptome of alpha synuclein transgenic mice exposed to a life-long HFD. Investigating individual transcript isoforms, differential gene expression, and co-expression clusters, we observed that transcriptional differences between wildtype and transgenic animals intensified in both regions under HFD. Both brainstem and hippocampus displayed strikingly similar transcriptomic perturbation patterns. Interestingly, expression differences resulted mainly from responses in wildtype animals to HFD, while these genes remained largely unchanged or were even slightly oppositely regulated by diet in transgenic animals. Genes and co-expressed gene groups exhibiting this dysregulation were linked to metabolic and mitochondrial pathways. Our findings propose failure of metabolic adaptions as potential explanation for accelerated disease unfolding under exposure to HFD. From the identified clusters of co-expressed genes, several candidates lend themselves to further functional investigations.