Misfolded alpha-synuclein in amyotrophic lateral sclerosis: Implications for diagnosis and treatment.
alpha-synuclein
amyotrophic lateral sclerosis
neurodegeneration
seed amplification assay
self-replicating proteins
Journal
European journal of neurology
ISSN: 1468-1331
Titre abrégé: Eur J Neurol
Pays: England
ID NLM: 9506311
Informations de publication
Date de publication:
25 Jan 2024
25 Jan 2024
Historique:
revised:
30
11
2023
received:
16
06
2023
accepted:
28
12
2023
medline:
25
1
2024
pubmed:
25
1
2024
entrez:
25
1
2024
Statut:
aheadofprint
Résumé
Alpha-synuclein (α-Syn) oligomers and fibrils have been shown to augment the aggregation of TAR DNA-binding Protein 43 (TDP-43) monomers in vitro, supporting the idea that TDP-43 proteinopathies such as ALS may be modulated by the presence of toxic forms of α-Syn 1. Recently, parkinsonian features were reported in a study of European patients 2 and Lewy bodies have been demonstrated pathologically in a similar series of patients 3. Based on these and other considerations, we sought to determine whether seed-competent α-Syn can be identified in spinal fluid of patients with ALS including familial, sporadic, and Guamanian forms of the disease. Based on the finding that α-Syn has been found to be a prion-like protein, we have utilized a validated α-Synuclein seed amplification assay to determine if seed-competent α-Syn could be detected in the spinal fluid of patients with ALS. Toxic species of α-Syn were detected in CSF in 18 of 127 ALS patients, 5 of whom were from Guam. Two out of twenty six samples from patients with C9orf72 variant ALS had positive seed-amplification assay (SAAs). No positive tests were noted in superoxide dismutase type 1 ALS subjects (n = 14). The SAA was negative in 31 control subjects. Our findings suggest that a sub-group of ALS occurs in which self-replicating α-Syn is detectable and likely contributes to its pathogenesis. This finding may have implications for the diagnosis and treatment of this disorder.
Sections du résumé
BACKGROUND
BACKGROUND
Alpha-synuclein (α-Syn) oligomers and fibrils have been shown to augment the aggregation of TAR DNA-binding Protein 43 (TDP-43) monomers in vitro, supporting the idea that TDP-43 proteinopathies such as ALS may be modulated by the presence of toxic forms of α-Syn 1. Recently, parkinsonian features were reported in a study of European patients 2 and Lewy bodies have been demonstrated pathologically in a similar series of patients 3. Based on these and other considerations, we sought to determine whether seed-competent α-Syn can be identified in spinal fluid of patients with ALS including familial, sporadic, and Guamanian forms of the disease.
METHODS
METHODS
Based on the finding that α-Syn has been found to be a prion-like protein, we have utilized a validated α-Synuclein seed amplification assay to determine if seed-competent α-Syn could be detected in the spinal fluid of patients with ALS.
RESULTS
RESULTS
Toxic species of α-Syn were detected in CSF in 18 of 127 ALS patients, 5 of whom were from Guam. Two out of twenty six samples from patients with C9orf72 variant ALS had positive seed-amplification assay (SAAs). No positive tests were noted in superoxide dismutase type 1 ALS subjects (n = 14). The SAA was negative in 31 control subjects.
CONCLUSIONS
CONCLUSIONS
Our findings suggest that a sub-group of ALS occurs in which self-replicating α-Syn is detectable and likely contributes to its pathogenesis. This finding may have implications for the diagnosis and treatment of this disorder.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e16206Informations de copyright
© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
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