Elevated Levels of α-Synuclein Oligomer in the Cerebrospinal Fluid of Drug-Naïve Patients with Parkinson's Disease

Park, Min Jeong; Cheon, Sang-Myung; Bae, Hye Ran; Kim, Sang Ho; Kim, Jae Woo

doi:10.3988/jcn.2011.7.4.215

Cited by 171 publications

(194 citation statements)

References 45 publications

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“…Confirming several studies showing relatively low CSF AS concentrations in both PD and DLB [731,[773][774][775], more recent ones reported significantly lower AS levels in PD [776,777] as well as in PD, DLB and MSA than in AD [777][778][779]. While CSF levels of AS oligomers were significantly increased in PD patients against controls [298,416,780], AD and progressive supranuclear palsy (PSP) [781], others were unanble to detect oligomeric AS in CSF [776]. Recent work detected alterations in AS phosphorylation (Ser129) in the CSF of PD patients [782].…”

Section: α-Synuclein As a Biomarker For Synucleinopathiessupporting

confidence: 61%

“…Ala30Pro (A30P), in a German kindred [288], shows similarities to PD but more severe pathology [289], and E46K or Glu46Lys [295]. Tg A53T mice develop a movement disorder with AS inclusions and loss of DAergic terminals, due to mitochondrial (mt) DNA damage [296] and mitochondrial autophagy [297], whereas double tg mice, also expressing BS, presented a milder phenoype [298]. The subcellular distribution of AS mutations, A30P and A53T, is influenced by its phosphorylation at Ser-129 [299], and acclerates neurodegeneration in a rat model of PD [300].…”

Section: It Improves Mitochondrial Dysfunction Altersmentioning

confidence: 99%

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The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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Section: α-Synuclein As a Biomarker For Synucleinopathiessupporting

confidence: 61%

Section: It Improves Mitochondrial Dysfunction Altersmentioning

confidence: 99%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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“…This limitation also applies to ELISA assays based on the same design principle. Although we were unable to detect oligomeric ␣-synuclein in CSF, two groups reported an increase in oligomers in PD patients (19,34). This is potentially surprising in light of our finding, as robust oligomer detection in itself would suggest that ␣-synuclein oligomers represent a sizeable portion of the total CSF ␣-synuclein pool in vivo.…”

Section: Volume 287 • Number 40 • September 28 2012contrasting

confidence: 50%

“…Elevated ␣-synuclein oligomers in human CSF, which are considered a portion of the total pool of ␣-synuclein species present in vivo, may be linked to the pathogenesis of PD and related synucleinopathies (19,34). Unexpectedly, our initial attempts to quantify oligomeric ␣-synuclein in human CSF using SynBa3-Tb/SynBa3-d2 were unsuccessful (data not shown).…”

Section: Figure 3 Determination Of ␣-Synuclein Tr-fret Assay Specifimentioning

confidence: 99%

“…However, an important limitation was also identified. As in earlier reports (33,34), our assay comprises a single ␣-synuclein monoclonal detection antibody in both donor and acceptor configurations. Although this arrangement begets specificity, it inherently disposes the interaction of oligomers with detection antibodies to competition with monomeric ␣-synuclein.…”

Section: Volume 287 • Number 40 • September 28 2012mentioning

confidence: 99%

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Novel One-step Immunoassays to Quantify α-Synuclein

Bidinosti

Shimshek

Mollenhauer

et al. 2012

Journal of Biological Chemistry

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Background: Robust assays for ␣-synuclein quantification are essential for Parkinson disease therapeutic development. Results: TR-FRET immunoassays were validated for total and oligomeric ␣-synuclein and used to screen small molecules and kinases that regulate ␣-synuclein expression. Conclusion: TR-FRET immunoassays are suitable for biomarker development and high-throughput screening. Significance: This is the first platform for large-scale drug discovery and for neuronal pathway analysis of ␣-synuclein expression regulation.

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Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease

et al. 2020

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IMPORTANCE This study evaluated nilotinib safety and its effects on biomarkers as a potential disease-modifying drug in Parkinson disease.OBJECTIVES To assess nilotinib effects on safety and pharmacokinetics and measure the change in exploratory biomarkers in patients with moderately severe Parkinson disease. DESIGN, SETTING, AND PARTICIPANTSThis was a single-center, phase 2, randomized, double-blind, placebo-controlled trial with 300 patients approached in clinic; of these, 200 declined to participate, 100 were screened, 25 were excluded, and 75 were randomized 1:1:1 into placebo; nilotinib, 150-mg; or nilotinib, 300-mg groups. Recruitment started on May 17, 2017, and ended April 28, 2018, and follow-up ended August 10, 2019. Parkinson disease was confirmed according to the UK Brain Bank diagnostic criteria and symptoms were stabilized with use of optimal levodopa and/or dopamine agonists and other medications used in Parkinson disease.INTERVENTIONS Nilotinib vs placebo, administered orally once daily for 12 months followed by a 3-month washout period.MAIN OUTCOMES AND MEASURES It was hypothesized that nilotinib is safe and can be detected in the cerebrospinal fluid, where it alters exploratory biomarkers via inhibition of Abelson tyrosine kinase and potentially improves clinical outcomes. RESULTSOf the 75 patients included in the study, 55 were men (73.3%); mean (SD) age was 68.4 (8.2) years. Doses of 150 or 300 mg of nilotinib were reasonably safe, although more serious adverse events were detected in the nilotinib (150 mg: 6 [24%]; 300 mg: 12 [48%]) vs placebo (4 [16%]) groups. The 150-mg nilotinib group showed an increase in cerebrospinal fluid levels of the dopamine metabolites homovanillic acid (159.80nM; 90% CI, 7.04-312.60nM; P = .04) and 3,4-dihydroxyphenylacetic acid (4.87nM; 90% CI, 1.51-8.23nM; P = .01), and the 300-mg nilotinib group showed an increase in 3,4-dihydroxyphenylacetic acid (7.52nM; 90% CI, 2.35-12.69nM; P = .01). The nilotinib 150-mg but not the nilotinib 300-mg group demonstrated a reduction of α-synuclein oligomers (−0.04 pg/mL; 90% CI, −0.08 to 0.01 pg/mL; P = .03). A significant reduction of hyperphosphorylated tau levels was seen in the nilotinib 150-mg (−10.04 pg/mL; 90% CI, −17.41 to −2.67 pg/mL; P = .01) and nilotinib 300-mg (−12.05 pg/mL; 90% CI, −19.21 to −4.90 pg/mL; P = .01) groups.CONCLUSIONS AND RELEVANCE In this study, nilotinib appeared to be reasonably safe and detectable in the cerebrospinal fluid. Exploratory biomarkers were altered in response to nilotinib. Taken together, these data will guide the development of a phase 3 study to investigate the effects of nilotinib therapy in patients with Parkinson disease. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02954978

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Elevated Levels of α-Synuclein Oligomer in the Cerebrospinal Fluid of Drug-Naïve Patients with Parkinson's Disease

Cited by 171 publications

References 45 publications

The role of α-synuclein in neurodegeneration — An update

The role of α-synuclein in neurodegeneration — An update

Novel One-step Immunoassays to Quantify α-Synuclein

Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease

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