Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Apr;141(4):491-510.
doi: 10.1007/s00401-020-02177-z. Epub 2020 Jun 30.

Vesicle trafficking and lipid metabolism in synucleinopathy

Saranna Fanning  1 , Dennis Selkoe  2 , Ulf Dettmer  3
Affiliations
Review

Vesicle trafficking and lipid metabolism in synucleinopathy

Saranna Fanning et al. Acta Neuropathol. 2021 Apr.

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.

Keywords: Alpha-synuclein; Lipids; Parkinson’s disease; Protein aggregation; Synucleinopathy; Vesicle trafficking.

PubMed Disclaimer

Conflict of interest statement

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

Figures

Fig. 1:
Fig. 1:
Contrasting non-fibrillar, lipid-rich (left) and ‘classical’, fibrillar (right) LBs. Non-fibrillar LBs might be precursors of fibrillar LBs.
Fig. 2:
Fig. 2:
Proposed roles for αS at synapses. See main text for details.
Fig. 3:
Fig. 3:
a. Proposed sites of αS interactions for non-synaptic membrane vesicles. b. Possible modes of aberrant αS-membrane interactions. See main text for key to circled numbers.
Fig. 4:
Fig. 4:
Different scenarios of how aberrant trafficking or composition of cellular vesicles may cause or aggravate αS dyshomeostasis, contributing to PD pathogenesis. The end point in all cases are αS membrane-rich and or fibrillar aggregates. See main text for further details.
Fig. 5:
Fig. 5:
Correcting GBA deficits to equilibrium restores physiologic GCase and repairs the GCase lysosomal pathway. It further prevents αS accumulation at membranes, accumulation of αS monomers as well as (downstream) oligomer formation/fibrillar aggregation.
Fig. 6 :
Fig. 6 :
SCD inhibition restores αS-Induced diglyceride (DG) accumulation in the ER, trafficking defects as well as increased triglycerides (TG) and lipid droplets. The treatment reduces clusters of vesicles when excess αS monomers accumulate and form cytoplasmic inclusions (as well as αS fibrillization that might be downstream). Decreased SCD activity prevents membrane defects, decreases αS phosphorylation and restores intact equilibria between αS monomers vs. physiological helical tetramers as well as cytosolic vs. membrane-associated αS.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Abeliovich A, Gitler AD (2016) Defects in trafficking bridge Parkinson’s disease pathology and genetics. Nature 539:207–216. doi: 10.1038/nature20414 - DOI - PubMed
    1. Abeliovich A, Schmitz Y, Fariñas I, Choi-Lundberg D, Ho WH, Castillo PE, et al. (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252 - PubMed
    1. Alvarez-Erviti L, Seow Y, Schapira AH, Gardiner C, Sargent IL, Wood MJA, Cooper JM (2011) Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiology of Disease 42:360–367. doi: 10.1016/j.nbd.2011.01.029 - DOI - PMC - PubMed
    1. Appel-Cresswell S, Vilarino-Guell C, Encarnacion M, Sherman H, Yu I, Shah B, et al. (2013) Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson’s disease. Mov Disord 28:811–813. doi: 10.1002/mds.25421 - DOI - PubMed
    1. Bae E-J, Lee H-J, Jang Y-H, Michael S, Masliah E, Min DS, Lee S-J (2014) Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates. Cell Death Differ 21:1132–1141. doi: 10.1038/cdd.2014.30 - DOI - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources