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Galectin-3 shapes toxic alpha-synuclein strains in Parkinson’s disease

García-Revilla, Juan LU ; Boza-Serrano, Antonio LU ; Jin, Yiyun ; Vadukul, Devkee M. ; Soldán-Hidalgo, Jesús LU ; Camprubí-Ferrer, Lluís LU ; García-Cruzado, Marta LU ; Martinsson, Isak LU ; Klementieva, Oxana LU orcid and Ruiz, Rocío , et al. (2023) In Acta Neuropathologica 146(1). p.51-75
Abstract

Parkinson’s Disease (PD) is a neurodegenerative and progressive disorder characterised by intracytoplasmic inclusions called Lewy bodies (LB) and degeneration of dopaminergic neurons in the substantia nigra (SN). Aggregated α-synuclein (αSYN) is known to be the main component of the LB. It has also been reported to interact with several proteins and organelles. Galectin-3 (GAL3) is known to have a detrimental function in neurodegenerative diseases. It is a galactose-binding protein without known catalytic activity and is expressed mainly by activated microglial cells in the central nervous system (CNS). GAL3 has been previously found in the outer layer of the LB in post-mortem brains. However, the role of GAL3 in PD is yet to be... (More)

Parkinson’s Disease (PD) is a neurodegenerative and progressive disorder characterised by intracytoplasmic inclusions called Lewy bodies (LB) and degeneration of dopaminergic neurons in the substantia nigra (SN). Aggregated α-synuclein (αSYN) is known to be the main component of the LB. It has also been reported to interact with several proteins and organelles. Galectin-3 (GAL3) is known to have a detrimental function in neurodegenerative diseases. It is a galactose-binding protein without known catalytic activity and is expressed mainly by activated microglial cells in the central nervous system (CNS). GAL3 has been previously found in the outer layer of the LB in post-mortem brains. However, the role of GAL3 in PD is yet to be elucidated. In post-mortem samples, we identified an association between GAL3 and LB in all the PD subjects studied. GAL3 was linked to less αSYN in the LB outer layer and other αSYN deposits, including pale bodies. GAL3 was also associated with disrupted lysosomes. In vitro studies demonstrate that exogenous recombinant Gal3 is internalised by neuronal cell lines and primary neurons where it interacts with endogenous αSyn fibrils. In addition, aggregation experiments show that Gal3 affects spatial propagation and the stability of pre-formed αSyn fibrils resulting in short, amorphous toxic strains. To further investigate these observations in vivo, we take advantage of WT and Gal3KO mice subjected to intranigral injection of adenovirus overexpressing human αSyn as a PD model. In line with our in vitro studies, under these conditions, genetic deletion of GAL3 leads to increased intracellular αSyn accumulation within dopaminergic neurons and remarkably preserved dopaminergic integrity and motor function. Overall, our data suggest a prominent role for GAL3 in the aggregation process of αSYN and LB formation, leading to the production of short species to the detriment of larger strains which triggers neuronal degeneration in a mouse model of PD.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Galectin-3 (GAL3), Lewy body (LB), Parkinson’s disease (PD), α-synuclein (αSYN)
in
Acta Neuropathologica
volume
146
issue
1
pages
25 pages
publisher
Springer
external identifiers
  • pmid:37202527
  • scopus:85159665280
ISSN
0001-6322
DOI
10.1007/s00401-023-02585-x
language
English
LU publication?
yes
id
1eb2438f-28bc-4a09-82ae-f4b495f621c6
date added to LUP
2023-09-25 11:11:13
date last changed
2024-04-19 01:25:23
@article{1eb2438f-28bc-4a09-82ae-f4b495f621c6,
  abstract     = {{<p>Parkinson’s Disease (PD) is a neurodegenerative and progressive disorder characterised by intracytoplasmic inclusions called Lewy bodies (LB) and degeneration of dopaminergic neurons in the substantia nigra (SN). Aggregated α-synuclein (αSYN) is known to be the main component of the LB. It has also been reported to interact with several proteins and organelles. Galectin-3 (GAL3) is known to have a detrimental function in neurodegenerative diseases. It is a galactose-binding protein without known catalytic activity and is expressed mainly by activated microglial cells in the central nervous system (CNS). GAL3 has been previously found in the outer layer of the LB in post-mortem brains. However, the role of GAL3 in PD is yet to be elucidated. In post-mortem samples, we identified an association between GAL3 and LB in all the PD subjects studied. GAL3 was linked to less αSYN in the LB outer layer and other αSYN deposits, including pale bodies. GAL3 was also associated with disrupted lysosomes. In vitro studies demonstrate that exogenous recombinant Gal3 is internalised by neuronal cell lines and primary neurons where it interacts with endogenous αSyn fibrils. In addition, aggregation experiments show that Gal3 affects spatial propagation and the stability of pre-formed αSyn fibrils resulting in short, amorphous toxic strains. To further investigate these observations in vivo, we take advantage of WT and Gal3KO mice subjected to intranigral injection of adenovirus overexpressing human αSyn as a PD model. In line with our in vitro studies, under these conditions, genetic deletion of GAL3 leads to increased intracellular αSyn accumulation within dopaminergic neurons and remarkably preserved dopaminergic integrity and motor function. Overall, our data suggest a prominent role for GAL3 in the aggregation process of αSYN and LB formation, leading to the production of short species to the detriment of larger strains which triggers neuronal degeneration in a mouse model of PD.</p>}},
  author       = {{García-Revilla, Juan and Boza-Serrano, Antonio and Jin, Yiyun and Vadukul, Devkee M. and Soldán-Hidalgo, Jesús and Camprubí-Ferrer, Lluís and García-Cruzado, Marta and Martinsson, Isak and Klementieva, Oxana and Ruiz, Rocío and Aprile, Francesco A. and Deierborg, Tomas and Venero, José Luis}},
  issn         = {{0001-6322}},
  keywords     = {{Galectin-3 (GAL3); Lewy body (LB); Parkinson’s disease (PD); α-synuclein (αSYN)}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{51--75}},
  publisher    = {{Springer}},
  series       = {{Acta Neuropathologica}},
  title        = {{Galectin-3 shapes toxic alpha-synuclein strains in Parkinson’s disease}},
  url          = {{http://dx.doi.org/10.1007/s00401-023-02585-x}},
  doi          = {{10.1007/s00401-023-02585-x}},
  volume       = {{146}},
  year         = {{2023}},
}