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
Recommended Citation
Smith, Richard; Hovren, Hanna; Bowser, Robert; Bakkar, Nadine; Garruto, Ralph; Ludolph, Albert; Ravits, John; Gaertner, Lia; Murphy, Davan; and Lebovitz, Russ, "Misfolded alpha-synuclein in amyotrophic lateral sclerosis: Implications for diagnosis and treatment." (2024). Translational Neuroscience. 2377.
https://scholar.barrowneuro.org/neurobiology/2377