1.
Differential Phospho‐Signatures in Blood Cells Identify LRRK2 G2019S Carriers in Parkinson's Disease
Garrido, Alicia; Santamaría, Enrique; Fernández‐Irigoyen, Joaquín ...
Movement disorders,
20/May , Letnik:
37, Številka:
5
Journal Article
Background
The clinicopathological phenotype of G2019S LRRK2‐associated Parkinson's disease (L2PD) is similar to idiopathic Parkinson's disease (iPD), and G2019S LRRK2 nonmanifesting carriers ...
(L2NMCs) are at increased risk for development of PD. With various therapeutic strategies in the clinical and preclinical pipeline, there is an urgent need to identify biomarkers that can aid early diagnosis and patient enrichment for ongoing and future LRRK2‐targeted trials.
Objective
The objective of this work was to investigate differential protein and phospho‐protein changes related to G2019S mutant LRRK2 in peripheral blood mononuclear cells from G2019S L2PD patients and G2019S L2NMCs, identify specific phospho‐protein changes associated with the G2019S mutation and with disease status, and compare findings with patients with iPD.
Methods
We performed an unbiased phospho‐proteomic study by isobaric label–based mass spectrometry using peripheral blood mononuclear cell group pools from a LRRK2 cohort from Spain encompassing patients with G2019S L2PD (n = 20), G2019S L2NMCs (n = 20), healthy control subjects (n = 30), patients with iPD (n = 15), patients with R1441G L2PD (n = 5), and R1441G L2NMCs (n = 3) (total N = 93).
Results
Comparing G2019S carriers with healthy controls, we identified phospho‐protein changes associated with the G2019S mutation. Moreover, we uncovered a specific G2019S phospho‐signature that changes with disease status and can discriminate patients with G2019S L2PD, G2019S L2NMCs, and healthy controls. Although patients with iPD showed a differential phospho‐proteomic profile, biological enrichment analyses revealed similar changes in deregulated pathways across the three groups.
Conclusions
We found a differential phospho‐signature associated with LRRK2 G2019S for which, consistent with disease status, the phospho‐profile from PD at‐risk G2019S L2NMCs was more similar to healthy controls than patients with G2019S L2PD with the manifested disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
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2.
Motor and nonmotor heterogeneity of LRRK2-related and idiopathic Parkinson's disease
Marras, Connie; Alcalay, Roy N.; Caspell-Garcia, Chelsea ...
Movement disorders,
08/2016, Letnik:
31, Številka:
8
Journal Article
ABSTRACT
Background
Parkinson's disease (PD) associated with LRRK2 mutations has been described as similar to idiopathic PD with minor clinical differences. No study has compared the clinical ...
features of LRRK2‐associated PD due to different mutations. The objective of this study was to compare LRRK2‐associated PD due to G2019S and G2385R mutations and to compare each to idiopathic PD.
Methods
Sites within the international LRRK2 Cohort Consortium undertook family‐based, community‐based, or clinic‐based studies to gather clinical data on manifesting carriers and patients with idiopathic PD.
Results
Five hundred sixteen PD patients with the G2019S mutation, 199 with the G2385R mutation, and 790 patients with idiopathic PD were included in the data set. Adjusted for age, sex, disease duration, and levodopa‐equivalent daily dose, mean MDS‐UPDRS part II or III scores and the frequency of motor fluctuations were higher in the G2385R mutation carriers than in either the G2019S mutation carriers or idiopathic PD patients. G2019S mutation carriers had significantly lower UPDRS part III scores than idiopathic PD patients. Both G2019S and G2385R mutation carriers had a higher proportion of the postural instability gait disorder phenotype compared with idiopathic PD patients. LRRK2 G2019S PD patients had better UPSIT scores and lower Geriatric Depression Scale scores than idiopathic PD patients in adjusted analyses.
Conclusions
G2385R and G2019S PD appear to have motor differences that may be explained by contrasting local treatment or measurement practices or differences in the biology of the disease. Longitudinal studies should evaluate whether progression is faster in G2385R mutation carriers compared with G2019S PD or idiopathic PD. © 2016 International Parkinson and Movement Disorder Society
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3.
Identification of blood serum micro-RNAs associated with idiopathic and LRRK2 Parkinson's disease
Botta-Orfila, Teresa; Morató, Xavier; Compta, Yaroslau ...
Journal of neuroscience research,
August 2014, Letnik:
92, Številka:
8
Journal Article
Blood‐cell‐free circulating micro‐RNAs (miRNAs) have been proposed as potential accessible biomarkers for neurodegenerative diseases such as Parkinson's disease (PD). Here we analyzed the serum ...
levels of 377 miRNAs in a discovery set of 10 idiopathic Parkinson's disease (IPD) patients, 10 PD patients carriers of the LRRK2 G2019S mutation (LRRK2 PD), and 10 controls by using real‐time quantitative PCR‐based TaqMan MicroRNA arrays. We detected candidate differentially expressed miRNAs, which were further tested in a first validation set consisting of 20 IPD, 20 LRRK2 PD, and 20 control samples. We found four statistically significant miRNAs that were downregulated in either LRRK2 or IPD (miR‐29a, miR‐29c, miR‐19a, and miR‐19b). Subsequently, we validated these findings in a third set of samples consisting of 65 IPD and 65 controls and confirmed the association of downregulated levels of miR‐29c, miR‐29a, and miR‐19b in IPD. Differentially expressed miRNAs are predicted to target genes belonging to pathways related to ECM–receptor interaction, focal adhesion, MAPK, Wnt, mTOR, adipocytokine, and neuron projection. Results from our exploratory study indicate that downregulated levels of specific circulating serum miRNAs are associated with PD and suggest their potential use as noninvasive biomarkers for PD. Future studies should further confirm the association of these miRNAs with PD. © 2014 Wiley Periodicals, Inc.
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4.
MicroRNA association with synucleinopathy conversion in rapid eye movement behavior disorder
Fernández-Santiago, Rubén; Iranzo, Alex; Gaig, Carles ...
Annals of neurology,
05/2015, Letnik:
77, Številka:
5
Journal Article
Recently, we reported downregulated circulating levels of the microRNAs miR‐19b, miR‐29a, and miR‐29c in Parkinson disease. Here we investigated the expression of these microRNAs in serum samples ...
from 56 patients with idiopathic rapid eye movement sleep behavior disorder, before and after their conversion into a synucleinopathy. Compared to controls, we found that the expression level of miR‐19b is downregulated in patients with idiopathic rapid eye movement sleep behavior disorder and antedates the diagnosis of Parkinson disease and dementia with Lewy bodies after 4.67 ± 2.61 years of follow‐up. Our findings indicate that dysregulation of the microRNA miR‐19b occurs in the prodromal stage of synucleinopathies. Ann Neurol 2015;77:895–901
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5.
Serum MicroRNAs Predict Isolated Rapid Eye Movement Sleep Behavior Disorder and Lewy Body Diseases
Soto, Marta; Iranzo, Alex; Lahoz, Sara ...
Movement disorders,
October 2022, Letnik:
37, Številka:
10
Journal Article
ABSTRACT
Background
Isolated rapid eye movement sleep behavior disorder (IRBD) is a well‐established clinical risk factor for Lewy body diseases (LBDs), such as Parkinson's disease (PD) and dementia ...
with Lewy bodies (DLB).
Objective
To elucidate whether serum microRNA (miRNA) deregulation in IRBD can antedate the diagnosis of LBD by performing a longitudinal study in different progression stages of IRBD before and after LBD diagnosis and assessing the predictive performance of differentially expressed miRNAs by machine learning–based modeling.
Methods
Using genome‐wide miRNA analysis and real‐time quantitative polymerase chain reaction validation, we assessed serum miRNA profiles from patients with IRBD stratified by dopamine transporter (DaT) single‐photon emission computed tomography into DaT‐negative IRBD (n = 17) and DaT‐positive IRBD (n = 21), IRBD phenoconverted into LBD (n = 13), and controls (n = 20). Longitudinally, we followed up the IRBD cohort by studying three time point serum samples over 26 months.
Results
We found sustained cross‐sectional and longitudinal deregulation of 12 miRNAs across the RBD continuum, including DaT‐negative IRBD, DaT‐positive IRBD, and LBD phenoconverted IRBD (let‐7c‐5p, miR‐19b‐3p, miR‐140, miR‐22‐3p, miR‐221‐3p, miR‐24‐3p, miR‐25‐3p, miR‐29c‐3p, miR‐361‐5p, miR‐425‐5p, miR‐4505, and miR‐451a) (false discovery rate P < 0.05). Age‐ and sex‐adjusted predictive modeling based on the 12 differentially expressed miRNA biosignatures discriminated IRBD and PD or DLB from controls with an area under the curve of 98% (95% confidence interval: 89–99%).
Conclusions
Besides clinical diagnosis of IRBD or imaging markers such as DaT single‐photon emission computed tomography, specific miRNA biosignatures alone hold promise as progression biomarkers for patients with IRBD for predicting PD and DLB clinical outcomes. Further miRNA studies in other PD at‐risk populations, such as LRRK2 mutation asymptomatic carriers or hyposmic subjects, are warranted. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
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6.
What have we learned from genome-wide association studies (GWAS) in Parkinson's disease?
Fernández-Santiago, Rubén; Sharma, Manu
Ageing research reviews,
August 2022, 2022-08-00, 20220801, Letnik:
79
Journal Article
After fifteen years of genome-wide association studies (GWAS) in Parkinson's disease (PD), what have we learned? Addressing this question will help catalogue the progress made towards elucidating ...
disease mechanisms, improving the clinical utility of the identified loci, and envisioning how we can harness the strides to develop translational GWAS strategies. Here we review the advances of PD GWAS made to date while critically addressing the challenges and opportunities for next-generation GWAS. Thus, deciphering the missing heritability in underrepresented populations is currently at the reach of hand for a truly comprehensive understanding of the genetics of PD across the different ethnicities. Moreover, state-of-the-art GWAS designs hold a true potential for enhancing the clinical applicability of genetic findings, for instance, by improving disease prediction (PD risk and progression). Lastly, advanced PD GWAS findings, alone or in combination with clinical and environmental parameters, are expected to have the capacity for defining patient enriched cohorts stratified by genetic risk profiles and readily available for neuroprotective clinical trials. Overall, envisioning future strategies for advanced GWAS is currently timely and can be instrumental in providing novel genetic readouts essential for a true clinical translatability of PD genetic findings.
•Mechanistic insights in PD continue being primarily driven by genetic discoveries.•Envisioning advanced GWAS can enhance clinical translatability of PD genetics.•Future GWAS will decipher the missing heritability in underrepresented populations.•Advanced GWAS can improve the prediction of PD risk and progression.•Next-generation GWAS can stratify patient enriched cohorts by genetic risk profiles.
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7.
The prodromal phase of leucine‐rich repeat kinase 2–associated Parkinson disease: Clinical and imaging Studies
Pont‐Sunyer, Claustre; Tolosa, Eduardo; Caspell‐Garcia, Chelsea ...
Movement disorders,
20/May , Letnik:
32, Številka:
5
Journal Article
ABSTRACT
Background: Asymptomatic, nonmanifesting carriers of leucine‐rich repeat kinase 2 mutations are at increased risk of developing PD. Clinical and neuroimaging features may be associated with ...
gene carriage and/or may demarcate individuals at greater risk for phenoconversion to PD.
Objectives: To investigate clinical and dopamine transporter single‐photon emission computed tomography imaging characteristics of leucine‐rich repeat kinase 2 asymptomatic carriers.
Methods: A total of 342 carriers' and 259 noncarriers' relatives of G2019S leucine‐rich repeat kinase 2/PD patients and 39 carriers' and 31 noncarriers' relatives of R1441G leucine‐rich repeat kinase 2/PD patients were evaluated. Motor and nonmotor symptoms were assessed using specific scales and questionnaires. Neuroimaging quantitative data were obtained in 81 carriers and compared with 41 noncarriers.
Results: G2019S carriers scored higher in motor scores and had lower radioligand uptake compared to noncarriers, but no differences in nonmotor symptoms scores were observed. R1441G carriers scored higher in motor scores, had lower radioligand uptake, and had higher scores in depression, dysautonomia, and Rapid Eye Movements Sleep Behavior Disorder Screening Questionnaire scores, but had better cognition scores than noncarriers. Among G2019S carriers, a group with “mild motor signs” was identified, and was significantly older, with worse olfaction and lower radioligand uptake.
Conclusions: G2019S and R1441G carriers differ from their noncarriers' relatives in higher motor scores and slightly lower radioligand uptake. Nonmotor symptoms were mild, and different nonmotor profiles were observed in G2019S carriers compared to R1441G carriers. A group of G2019S carriers with known prodromal features was identified. Longitudinal studies are required to determine whether such individuals are at short‐term risk of developing overt parkinsonism. © 2017 International Parkinson and Movement Disorder Society
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8.
Increased Phospho‐AKT in Blood Cells from LRRK2 G2019S Mutation Carriers
Garrido, Alicia; Pérez‐Sisqués, Leticia; Simonet, Cristina ...
Annals of neurology,
November 2022, Letnik:
92, Številka:
5
Journal Article
The purpose of this study was to investigate whether differential phosphorylation states of blood markers can identify patients with LRRK2 Parkinson's disease (PD). We assessed ...
phospho(P)‐Ser‐935‐LRRK2 and P‐Ser‐473‐AKT levels in peripheral blood cells from patients with G2019S LRRK2‐associated PD (L2PD, n = 31), G2019S LRRK2 non‐manifesting carriers (L2NMC, n = 26), idiopathic PD (iPD, n = 25), and controls (n = 40, total n = 122). We found no differences at P‐Ser‐935‐LRRK2 between groups but detected a specific increase of P‐Ser‐473‐AKT levels in all G2019S carriers, either L2PD or L2NMC, absent in iPD. Although insensitive to LRRK2 inhibition, our study identifies P‐Ser‐473‐AKT as an endogenous candidate biomarker for peripheral inflammation in G2019S carriers using accessible blood cells. ANN NEUROL 2022;92:888–894
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9.
α‐synuclein (SNCA) but not dynamin 3 (DNM3) influences age at onset of leucine‐rich repeat kinase 2 (LRRK2) Parkinson's disease in Spain
Fernández‐Santiago, Rubén; Garrido, Alicia; Infante, Jon ...
Movement disorders,
April 2018, 2018-04-00, 20180401, Letnik:
33, Številka:
4
Journal Article
ABSTRACT
Objectives: A recent study showed that Arab‐Berbers GG homozygous at rs2421947(C/G) in the dynamin 3 gene (DNM3) had 12.5 years earlier age at onset of leucine‐rich repeat kinase 2 ...
(LRRK2)‐associated Parkinson's disease (PD) (L2PD). We explored whether this variant modulates the L2PD age at onset in Spain.
Methods: We genotyped rs2421947 in 329 participants (210 L2PD patients, 119 L2PD nonmanifesting p.G2019S carriers), and marker rs356219 (A/G) in the α‐synuclein gene (SNCA).
Results: By Kaplan Meier and Cox regression analyses, we did not find an association of the DNM3 polymorphism with L2PD age at onset. However, we found an association of the SNCA marker with up to an 11 years difference in the L2PD median age at onset (58 years for GG carriers vs 69 years for AA).
Conclusion: Our results indicate that SNCA rs356219 but not dynamin 3 DNM3 rs2421947 modifies the penetrance of the mutation G2019S in the Spanish population by influencing the L2PD age at onset. These findings suggest that different genetic modifiers may influence the L2PD age at onset in different populations. © 2018 International Parkinson and Movement Disorder Society
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10.
The MC1R melanoma risk variant p.R160W is associated with Parkinson disease
Tell-Marti, Gemma; Puig-Butille, Joan Anton; Potrony, Miriam ...
Annals of neurology,
05/2015, Letnik:
77, Številka:
5
Journal Article
Epidemiological studies have reported the co‐occurrence of Parkinson disease (PD) and melanoma. Common genetic variants in the MC1R (melanocortin 1 receptor) gene, which determines skin and hair ...
color, are associated with melanoma. Here we investigated whether genetic variants in MC1R modulate the risk of PD by sequencing the entire gene in 870 PD patients and 736 controls ascertained from Spain. We found that the MC1R variant p.R160W (rs1805008) is marginally associated with PD (odds ratio = 2.10, gender‐ and age‐adjusted p = 0.009, Bonferroni‐corrected p = 0.063). Our results suggest that MC1R genetic variants modulate the risk of PD disease in the Spanish population. Ann Neurol 2015;77:889–894
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