Misfolded alpha-synuclein in amyotrophic lateral sclerosis: Implications for diagnosis and treatment.

Document Type

Article

Abstract

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. Recently, parkinsonian features were reported in a study of European patients and Lewy bodies have been demonstrated pathologically in a similar series of patients. 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: 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: 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 assays (SAAs). No positive tests were noted in superoxide dismutase type 1 ALS subjects (n = 14). The SAA was negative in 31 control subjects.

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.

Keywords

Humans, alpha-Synuclein, Amyotrophic Lateral Sclerosis, Lewy Bodies, Superoxide Dismutase-1

Medical Subject Headings

Humans; alpha-Synuclein; Amyotrophic Lateral Sclerosis; Lewy Bodies; Superoxide Dismutase-1

Publication Date

4-1-2024

Publication Title

European journal of neurology : the official journal of the European Federation of Neurological Societies

ISSN

1468-1331

Volume

31

Issue

4

First Page

16206

Last Page

16206

PubMed ID

38270442

Digital Object Identifier (DOI)

10.1111/ene.16206

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