Vesicle trafficking and lipid metabolism in synucleinopathy

Abstract

The neuronal protein α-synuclein (αS) is central to the pathogenesis of Parkinson’s disease and other progressive brain diseases such as Lewy body dementia and multiple system atrophy. These diseases, collectively referred to as ‘synucleinopathies’, have long been considered purely proteinopathies: diseases characterized by the misfolding of a protein into small and large aggregates mainly consisting of that protein (in this case: α-synuclein). However, recent morphological insights into Lewy bodies, the hallmark neuropathology of human synucleinopathies, suggests these lesions are also rich in vesicles and other membranous organelles. Moreover, αS physiology and pathology are both strongly associated with various aspects of intracellular vesicle trafficking and lipid biology. αS physiologically binds to synaptic and other small vesicles, and several functions of αS in regulating vesicle biology have been proposed. Familial PD-linked αS excess and missense mutations have been shown to impair vesicle trafficking and alter lipid homeostasis. On the other hand, vesicle trafficking and lipid-related genes have emerged as Parkinson’s risk factors, suggesting a bidirectional relationship. The answer to the question “Does abnormal αS accumulation cause impaired vesicle trafficking and lipid dyshomeostasis or is αS aggregation the consequence of such impairments?” may be “Both”. Here, we review current knowledge of the αS-lipid and αS-vesicle trafficking interplay, with a special focus on Parkinson’s disease and Lewy body dementia.

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Acknowledgements

We are grateful to Gina Dove and Renee Brathwaite for administrative support. We thank Tom DiCesare for the final illustrations. The αS-related work of our groups is supported by NIH Grants NS099328 (to UD) and NS083845 (to DS) and a grant by the Michael J Fox Foundation (to SF).

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SF and UD did the literature search and planned the manuscript, SF and UD drafted the figures, SF, DS and UD wrote and critically revised the manuscript.

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Correspondence to Saranna Fanning or Dennis Selkoe or Ulf Dettmer.

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DS is a director and consultant to Prothena Biosciences. The other authors declare no conflict of interest.

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Fanning, S., Selkoe, D. & Dettmer, U. Vesicle trafficking and lipid metabolism in synucleinopathy. Acta Neuropathol (2020). https://doi.org/10.1007/s00401-020-02177-z

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Keywords

  • Parkinson’s disease
  • Synucleinopathy
  • Alpha-synuclein
  • Vesicle trafficking
  • Lipids
  • Protein aggregation