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How is alpha-synuclein cleared from the cell?

Stefanis, Leonidas; Emmanouilidou, Evangelia; Pantazopoulou, Marina; Kirik, Deniz LU ; Vekrellis, Kostas and Tofaris, George K. (2019) In Journal of Neurochemistry
Abstract

The levels and conformers of alpha-synuclein are critical in the pathogenesis of Parkinson's Disease and related synucleinopathies. Homeostatic mechanisms in protein degradation and secretion have been identified as regulators of alpha-synuclein at different stages of its intracellular trafficking and transcellular propagation. Here we review pathways involved in the removal of various forms of alpha-synuclein from both the intracellular and extracellular environment. Proteasomes and lysosomes are likely to play complementary roles in the removal of intracellular alpha-synuclein species, in a manner that depends on alpha-synuclein post-translational modifications. Extracellular alpha-synuclein is cleared by extracellular proteolytic... (More)

The levels and conformers of alpha-synuclein are critical in the pathogenesis of Parkinson's Disease and related synucleinopathies. Homeostatic mechanisms in protein degradation and secretion have been identified as regulators of alpha-synuclein at different stages of its intracellular trafficking and transcellular propagation. Here we review pathways involved in the removal of various forms of alpha-synuclein from both the intracellular and extracellular environment. Proteasomes and lysosomes are likely to play complementary roles in the removal of intracellular alpha-synuclein species, in a manner that depends on alpha-synuclein post-translational modifications. Extracellular alpha-synuclein is cleared by extracellular proteolytic enzymes, or taken up by neighboring cells, especially microglia and astrocytes, and degraded within lysosomes. Exosomes, on the other hand, represent a vehicle for egress of excess burden of the intracellular protein, potentially contributing to the transfer of alpha-synuclein between cells. Dysfunction in any one of these clearance mechanisms, or a combination thereof, may be involved in the initiation or progression of Parkinson's disease, whereas targeting these pathways may offer an opportunity for therapeutic intervention. (Figure presented.).

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author
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
alpha-synuclein, degradation, exosomes, lysosomes, proteasome, ubiquitin
in
Journal of Neurochemistry
publisher
Wiley-Blackwell
external identifiers
  • scopus:85065513129
ISSN
0022-3042
DOI
10.1111/jnc.14704
language
English
LU publication?
yes
id
54586936-588f-44ab-a827-87b6c101c543
date added to LUP
2019-06-04 12:14:12
date last changed
2019-10-08 03:53:40
@article{54586936-588f-44ab-a827-87b6c101c543,
  abstract     = {<p>The levels and conformers of alpha-synuclein are critical in the pathogenesis of Parkinson's Disease and related synucleinopathies. Homeostatic mechanisms in protein degradation and secretion have been identified as regulators of alpha-synuclein at different stages of its intracellular trafficking and transcellular propagation. Here we review pathways involved in the removal of various forms of alpha-synuclein from both the intracellular and extracellular environment. Proteasomes and lysosomes are likely to play complementary roles in the removal of intracellular alpha-synuclein species, in a manner that depends on alpha-synuclein post-translational modifications. Extracellular alpha-synuclein is cleared by extracellular proteolytic enzymes, or taken up by neighboring cells, especially microglia and astrocytes, and degraded within lysosomes. Exosomes, on the other hand, represent a vehicle for egress of excess burden of the intracellular protein, potentially contributing to the transfer of alpha-synuclein between cells. Dysfunction in any one of these clearance mechanisms, or a combination thereof, may be involved in the initiation or progression of Parkinson's disease, whereas targeting these pathways may offer an opportunity for therapeutic intervention. (Figure presented.).</p>},
  author       = {Stefanis, Leonidas and Emmanouilidou, Evangelia and Pantazopoulou, Marina and Kirik, Deniz and Vekrellis, Kostas and Tofaris, George K.},
  issn         = {0022-3042},
  keyword      = {alpha-synuclein,degradation,exosomes,lysosomes,proteasome,ubiquitin},
  language     = {eng},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Neurochemistry},
  title        = {How is alpha-synuclein cleared from the cell?},
  url          = {http://dx.doi.org/10.1111/jnc.14704},
  year         = {2019},
}