SNCA variants and alpha-synuclein level in CD45+ blood cells in Parkinson’s disease

Anton, Emil; Kulabukhova, D. G.; Garaeva, Luiza; Senkevich, Konstantin; Verbitskaya, E.; Николаев, Михаил; Andoskin, P.; Kopytova, Alena E.; Milyukhina, I. V.; Yakimovskii, A. F.; Timofeeva, A. A.; Прахова, Л. Н.; Ilves, A. G.; Vlasova, Irina A.; Pchelina, Sofya

doi:10.1016/j.jns.2018.10.002

Cited by 18 publications

(12 citation statements)

References 30 publications

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“…Nilotinib significantly reduced the concentration of alpha-synuclein that is elevated in the blood of PD patients. [48][49][50][51] These results are consistent with our previous findings that demonstrated Nilotinib effects on lowering blood alpha-synuclein in mice. 7 There is evidence that autophagy is disregulated in the blood of PD patients, [52][53][54][55] and the effects of Nilotinib on autophagy may underlie its effects on plasma alphasynuclein.…”

Section: Discussionsupporting

confidence: 92%

“…Oligomeric alpha‐synuclein was not detected in the plasma, but we detected a significant effect on total alpha‐synuclein levels with lower single doses (150 and 200 mg) of Nilotinib. Nilotinib significantly reduced the concentration of alpha‐synuclein that is elevated in the blood of PD patients . These results are consistent with our previous findings that demonstrated Nilotinib effects on lowering blood alpha‐synuclein in mice .…”

Section: Discussionsupporting

confidence: 92%

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Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Pagán

Hebron

Wilmarth

et al. 2019

Pharmacology Res & Perspec

111

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Nilotinib is a broad‐based tyrosine kinase inhibitor with the highest affinity to inhibit Abelson (c‐Abl) and discoidin domain receptors ( DDR 1/2). Preclinical evidence indicates that Nilotinib reduces the level of brain alpha‐synuclein and attenuates inflammation in models of Parkinson's disease ( PD ). We previously showed that Nilotinib penetrates the blood‐brain barrier ( BBB ) and potentially improves clinical outcomes in individuals with PD and dementia with Lewy bodies ( DLB ). We performed a physiologically based population pharmacokinetic/pharmacodynamic (pop PK / PD ) study to determine the effects of Nilotinib in a cohort of 75 PD participants. Participants were randomized (1:1:1:1:1) into five groups (n = 15) and received open‐label random single dose ( RSD ) 150:200:300:400 mg Nilotinib vs placebo. Plasma and cerebrospinal fluid ( CSF ) were collected at 1, 2, 3, and 4 hours after Nilotinib administration. The results show that Nilotinib enters the brain in a dose‐independent manner and 200 mg Nilotinib increases the level of 3,4‐Dihydroxyphenylacetic acid ( DOPAC ) and homovanillic acid ( HVA ), suggesting alteration to dopamine metabolism. Nilotinib significantly reduces plasma total alpha‐synuclein and appears to reduce CSF oligomeric: total alpha‐synuclein ratio. Furthermore, Nilotinib significantly increases the CSF level of triggering receptors on myeloid cells ( TREM )‐2, suggesting an anti‐inflammatory effect. Taken together, 200 mg Nilotinib appears to be an optimal single dose that concurrently reduces inflammation and engages surrogate disease biomarkers, including dopamine metabolism and alpha‐synuclein.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Pagán

Hebron

Wilmarth

et al. 2019

Pharmacology Res & Perspec

111

View full text Add to dashboard Cite

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“…Previous studies have shown the rs356219/G was a significant risk for PD in different populations (Mata et al, 2010; Han et al, 2015; Emelyanov et al, 2018). It has been found that PD patients with rs356219/G had earlier onset age (Brockmann et al, 2013) and worse cognitive function (Campelo et al, 2017), probably affected by the distinction of SNCA expression in brain regions, blood, and plasma (Lesage and Brice, 2012; Brockmann et al, 2013; Burciu et al, 2018), whereas it was firstly shown in our study that rs356219/G reduces the risk of disease progression and cognitive impairment, which was not contradictory with previous studies.…”

Section: Discussionmentioning

confidence: 93%

Variants in the SNCA Locus Are Associated With the Progression of Parkinson's Disease

Luo

Niu

et al. 2019

Front. Aging Neurosci.

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Background: Genetic factors have a well-known influence on Parkinson's disease (PD) susceptibility; however, no previous studies have investigated the influence of SNCA mutations on the natural history of PD using a prospective follow-up study. The aim of this study was to assess the risk factors of variation of SNCA on the prognosis symptoms of PD patients. Methods: Fifty PD patients were recruited with 38 v-PSG confirmed PD+RBD patients, and the median follow-up period was 30 months. All patients underwent a comprehensive clinical evaluation at baseline and follow-up, and six SNPs of SNCA (rs356165, rs3857053, rs1045722, rs894278, rs356186, and rs356219) were analyzed. Cox proportional hazards regression models and Kaplan–Meier plot analysis were used to assess the associations between the SNCA variation and the primary and secondary progression outcomes. Results: Based on the clinical assessment, we found that hyposmia was substantially easier to aggravate. Regression analysis showed that patients with the T allele of rs1045722 and the G allele of rs356219 presented a 34 and 20% decreased risk of progression to the H-Y stage, respectively ( p = 0.022; p = 0.005). While for rs894278, G allele patients showed a 47% decreased risk of olfactory dysfunction ( p = 0.029). Further subgroup analysis showed that PD+RBD patients with rs356219/G exhibited a 30% and 20% decreased risk of progression on the H-Y stage and MoCA score ( p = 0.038; p = 0.045). Conclusions: Our results indicated that genetic variation in SNCA may contribute to variability natural progression of PD and could possibly be used as a prognostic marker.

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“…Despite the amount of research on this neurodegenerative disease, its origin remains unclear. Only 5-10% of cases have a genetic background [2][3][4][5], while the rest are of idiopathic origin [6], although some risk factors have been identified, such as age, environmental toxins, and infections [7,8].…”

Section: Introductionmentioning

confidence: 99%

Chronic Systemic Inflammation Exacerbates Neurotoxicity in a Parkinson’s Disease Model

Ugalde‐Muñiz

Fetter-Pruneda

Navarro

et al. 2020

Oxidative Medicine and Cellular Longevity

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Systemic inflammation is a crucial factor for microglial activation and neuroinflammation in neurodegeneration. This work is aimed at assessing whether previous exposure to systemic inflammation potentiates neurotoxic damage by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and how chronic systemic inflammation participates in the physiopathological mechanisms of Parkinson’s disease. Two different models of systemic inflammation were employed to explore this hypothesis: a single administration of lipopolysaccharide (sLPS; 5 mg/kg) and chronic exposure to low doses (mLPS; 100 μg/kg twice a week for three months). After three months, both groups were challenged with MPTP. With the sLPS administration, Iba1 staining increased in the striatum and substantia nigra, and the cell viability lowered in the striatum of these mice. mLPS alone had more impact on the proinflammatory profile of the brain, steadily increasing TNFα levels, activating microglia, reducing BDNF, cell viability, and dopamine levels, leading to a damage profile similar to the MPTP model per se. Interestingly, mLPS increased MAO-B activity possibly conferring susceptibility to MPTP damage. mLPS, along with MPTP administration, exacerbated the neurotoxic effect. This effect seemed to be coordinated by microglia since minocycline administration prevented brain TNFα increase. Coadministration of sLPS with MPTP only facilitated damage induced by MPTP without significant change in the inflammatory profile. These results indicate that chronic systemic inflammation increased susceptibility to MPTP toxic effect and is an adequate model for studying the impact of systemic inflammation in Parkinson’s disease.

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SNCA variants and alpha-synuclein level in CD45+ blood cells in Parkinson’s disease

Cited by 18 publications

References 30 publications

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Variants in the SNCA Locus Are Associated With the Progression of Parkinson's Disease

Chronic Systemic Inflammation Exacerbates Neurotoxicity in a Parkinson’s Disease Model

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