Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising disease-modifying therapy for LRRK2-associated Parkinson's disease (L2PD) and idiopathic PD. However, pharmacodynamic readouts and progression biomarkers for clinical trials aiming for disease modification are insufficient, given that no endogenous marker reflecting enhanced kinase activity of the most common LRRK2 G2019S mutation has yet been reported in L2PD patients.Using phospho-/proteomic analyses, we assessed the impact of LRRK2-activating mutations in peripheral blood mononuclear cells from an LRRK2 clinical cohort from Spain (n = 174). The study groups encompassed G2019S L2PD patients (n = 37), non-manifesting LRRK2 mutation carriers of G2019S (here termed G2019S L2NMCs) (n = 27), R1441G L2PD patients (n = 14), R1441G L2NMCs (n = 11), idiopathic PD patients (n = 40) and healthy controls (n = 45).We identified 207 differentially regulated proteins in G2019S L2PD compared with controls (39 upregulated and 168 downregulated) and 67 in G2019S L2NMCs (10 upregulated and 57 downregulated). G2019S downregulated proteins affected the endolysosomal pathway, proteostasis and mitochondria, e.g. ATIC, RAB9A or LAMP1. At the phospho-proteome level, we observed increases in endogenous phosphorylation levels of pSer106 RAB12 in G2019S carriers, which were validated by immunoblotting after 1 year of follow-up (n = 48). Freshly collected peripheral blood mononuclear cells from three G2019S L2PD, one R1441G L2PD, one idiopathic PD and five controls (n = 10) showed strong diminishment of pSer106 RAB12 phosphorylation levels after in vitro administration of the MLi-2 LRRK2 inhibitor. Using machine learning, we identified an 18-feature G2019S phospho-/protein signature discriminating G2019S L2PD, L2NMCs and controls with 96% accuracy that was correlated with disease severity, i.e. UPDRS-III motor scoring.Using easily accessible peripheral blood mononuclear cells from a LRRK2 clinical cohort, we identified elevated levels of pSer106 RAB12 as an endogenous biomarker of G2019S carriers. Our data suggest that monitoring pSer106 RAB12 phosphorylation could be a relevant biomarker for tracking LRRK2 activation, particularly in G2019S carriers. Future work might determine whether pSer106 RAB12 could help with patient enrichment and monitoring drug efficacy in LRRK2 clinical trials. The LRRK2 activating mutation G2019S is the most frequent genetic cause of Parkinson's disease. Through phospho-proteome analysis of blood, Cort & eacute;s et al. identify elevated phospho-RAB12 levels as an endogenous biomarker of G2019S mutation carriers, with potential utility in clinical trials.

Background: alpha-Synuclein (SNCA) gene hypomethylation was reported in idiopathic Parkinson's disease (iPD). Based on a high clinical resemblance between iPD and leucine-rich repeat kinase 2 (LRRK2)-driven Parkinson's disease (L2PD), we investigated the epigenetic status of SNCA in an extensive LRRK2 clinical cohort from Spain. Methods: We assessed the methylation levels of 23 CpG sites in the SNCA promoter region using peripheral blood DNA from L2PD patients (n = 151), LRRK2 nonmanifesting carriers (n = 55), iPD patients (n = 115), and healthy control subjects (n = 154) (total: N = 475). Results: Compared with control subjects, we found significant SNCA hypomethylation in 11 of 23 CpGs in L2PD (48%), whereas 22 CpGs (96%) were hypomethylated in iPD. In line with a healthy status, asymptomatic mutation carriers had similar SNCA methylation profiles to control subjects. Conclusions: This study shows for the first time that SNCA hypomethylation occurs in patients with L2PD. Further studies addressing SNCA methylation status in additional worldwide LRRK2 cohorts are warranted. (c) 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Over the last two decades there have been meaningful developments on biomarkers of neurodegenerative diseases, extensively (but not solely) focusing on their proteinopathic nature. Accordingly, in Alzheimer's disease determination of levels of total and phosphorylated tau (τ and p-τ, usually p-τ181) along with amyloid-beta1-42 (Aβ1-42) by immunodetection in cerebrospinal fluid (CSF) and currently even in peripheral blood, have been widely accepted and introduced to routine diagnosis. In the case of Parkinson's disease, α-synuclein as a potential biomarker (both for diagnosis and progression tracking) has proved more elusive under the immunodetection approach. In recent years, the emergence of the so-called seed amplification assays is proving to be a game-changer, with mounting evidence under different technical approaches and using a variety of biofluids or tissues, yielding promising diagnostic accuracies. Currently the least invasive but at once more reliable source of biosamples and techniques are being sought. Here we overview these advances.

Clinical and cognitive progression in alpha-synucleinopathies is highly heterogeneous. While some patients remain stable over long periods of time, other suffer early dementia or fast motor deterioration. Sleep disturbances and nocturnal blood pressure abnormalities have been identified as independent risk factors for clinical progression but a mechanistic explanation linking both aspects is lacking. We hypothesize that impaired glymphatic system might play a key role on clinical progression. Glymphatic system clears brain waste during specific sleep stages, being blood pressure the motive force that propels the interstitial fluid through brain tissue to remove protein waste. Thus, the combination of severe sleep alterations, such as REM sleep behavioral disorder, and lack of the physiological nocturnal decrease of blood pressure due to severe dysautonomia may constitute the perfect storm for glymphatic failure, causing increased abnormal protein aggregation and spreading. In Lewy body disorders (Parkinson's disease and dementia with Lewy bodies) the increment of intraneuronal alpha-synuclein and extracellular amyloid-β would lead to cognitive deterioration, while in multisystemic atrophy, increased pathology in oligodendroglia would relate to the faster and malignant motor progression. We present a research model that may help in developing studies aiming to elucidate the role of glymphatic function and associated factors mainly in alpha-synucleinopathies, but that could be relevant also for other protein accumulation-related neurodegenerative diseases. If the model is proven to be useful could open new lines for treatments targeting glymphatic function (for example through control of nocturnal blood pressure) with the objective to ameliorate cognitive and motor progression in alpha-synucleinopathies.

Nuclear depletion, abnormal modification, and cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) are linked to a group of fatal neurodegenerative diseases called TDP-43 proteinopathies, which include amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Although our understanding of the physiological function of TDP-43 is rapidly advancing, the molecular mechanisms associated with its pathogenesis remain poorly understood. Accumulating evidence suggests that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are important players in TDP-43 pathology. However, while neurons derived from autopsied ALS and FTLD patients revealed TDP-43 deposits in the ER and displayed UPR activation, data originated from in vitro and in vivo TDP-43 models produced contradictory results. In this review, we will explore the complex interplay between TDP-43 pathology, ER stress, and the UPR by breaking down the evidence available in the literature and addressing the reasons behind these discrepancies. We also highlight underexplored areas and key unanswered questions in the field. A better synchronization and integration of methodologies, models, and mechanistic pathways will be crucial to discover the true nature of the TDP-43 and ER stress relationship and, ultimately, to uncover the full therapeutic potential of the UPR.

We present here PhotoGal4, a phytochrome B-based optogenetic switch for fine-tuned spatiotemporal control of gene expression in Drosophila explants. This switch integrates the light-dependent interaction between phytochrome B and PIF6 from plants with regulatory elements from the yeast Gal4/UAS system. We found that PhotoGal4 efficiently activates and deactivates gene expression upon red- or far-red-light irradiation, respectively. In addition, this optogenetic tool reacts to different illumination conditions, allowing for fine modulation of the light-dependent response. Importantly, by simply focusing a laser beam, PhotoGal4 induces intricate patterns of expression in a customized manner. For instance, we successfully sketched personalized patterns of GFP fluorescence such as emoji-like shapes or letterform logos in Drosophila explants, which illustrates the exquisite precision and versatility of this tool. Hence, we anticipate that PhotoGal4 will expand the powerful Drosophila toolbox and will provide a new avenue to investigate intricate and complex problems in biomedical research.

BackgroundSelf-assembly of the amyloid-β (Aβ) peptide into aggregates, ranging from small oligomers to amyloid fibrils, is fundamentally linked with Alzheimer’s disease (AD). However it is clear that not all forms of Aβ are equally harmful, and that linking a specific aggregate to toxicity also depends on the assays and model systems used [1, 2]. Indeed, though a central postulate of the amyloid cascade hypothesis, there remain many gaps in our understanding regarding the links between Aβ deposition and neurodegeneration.MethodsIn this study we utilized BRI2-Aβ fusion technology and rAAV2/1 based somatic brain transgenesis to examine Aβ aggregates that form from selective expression of individual mutant Aβ species in vivo . In parallel we generated PhiC31-based transgenic Drosophila melanogaster expressing WT and mutant Aβ40 and Aβ42, fused to the Argos signal peptide and placed under the GAL4-upstream activation sequence (UAS) expression system in order to assess the extent of Aβ42-induced toxicity as well as to interrogate the combined effect of different forms of Aβ40 and Aβ42 species.ResultsWhen expressed in the mouse brain for 6 months, Aβ42 E22G, Aβ42 E22Q/D23N, and Aβ42 WT formed amyloid aggregates consisting of some diffuse material as well as cored plaques, whereas other mutants formed predominantly diffuse amyloid deposits. Moreover, while Aβ40WT showed no distinctive phenotype, Aβ40 E22G and E22Q/D23N formed unique aggregates that accumulated in mouse brains. This is the first evidence that mutant Aβ40 overexpression leads to deposition under certain conditions. Interestingly, we found that mutant Aβ42 E22G, E22Q, and S26C, but not Aβ40, were toxic to the eye of the flies and exacerbated their behavior. In contrast, flies expressing a copy of Aβ40 (wild type [WT] or mutants) in addition to Aβ42 WT, showed improved phenotypes, suggesting possible protective qualities for Aβ40.ConclusionsThese studies suggest that some Aβ40 mutants form unique amyloid aggregates in mouse brains, despite being protective against Aβ42 toxicity in Drosophila , which highlights the significance of using different systems for a better understanding of AD pathogenicity and more accurate screening for new potential therapies.

Processing of amyloid-β (Aβ) precursor protein (APP) by γ-secretase produces multiple species of Aβ: Aβ40, short Aβ peptides (Aβ37–39), and longer Aβ peptides (Aβ42–43). γ-Secretase modulators, a class of Alzheimer’s disease therapeutics, reduce production of the pathogenic Aβ42 but increase the relative abundance of short Aβ peptides. To evaluate the pathological relevance of these peptides, we expressed Aβ36–40 and Aβ42–43 in Drosophila melanogaster to evaluate inherent toxicity and potential modulatory effects on Aβ42 toxicity. In contrast to Aβ42, the short Aβ peptides were not toxic and, when coexpressed with Aβ42, were protective in a dose-dependent fashion. In parallel, we explored the effects of recombinant adeno-associated virus–mediated expression of Aβ38 and Aβ40 in mice. When expressed in nontransgenic mice at levels sufficient to drive Aβ42 deposition, Aβ38 and Aβ40 did not deposit or cause behavioral alterations. These studies indicate that treatments that lower Aβ42 by raising the levels of short Aβ peptides could attenuate the toxic effects of Aβ42.

The ability to manipulate expression of exogenous genes in particular regions of living organisms has profoundly transformed the way we study biomolecular processes involved in both normal development and disease. Unfortunately, most of the classical inducible systems lack fine spatial and temporal accuracy, thereby limiting the study of molecular events that strongly depend on time, duration of activation, or cellular localization. By exploiting genetically engineered photo sensing proteins that respond to specific wavelengths, we can now provide acute control of numerous molecular activities with unprecedented precision. In this review, we present a comprehensive breakdown of all of the current optogenetic systems adapted to regulate gene expression in both unicellular and multicellular organisms. We focus on the advantages and disadvantages of these different tools and discuss current and future challenges in the successful translation to more complex organisms.

The ability to manipulate expression of exogenous genes in particular regions of living organisms has profoundly transformed the way we study biomolecular processes involved in both normal development and disease. Unfortunately, most of the classical inducible systems lack fine spatial and temporal accuracy, thereby limiting the study of molecular events that strongly depend on time, duration of activation, or cellular localization. By exploiting genetically engineered photo sensing proteins that respond to specific wavelengths, we can now provide acute control of numerous molecular activities with unprecedented precision. In this review, we present a comprehensive breakdown of all of the current optogenetic systems adapted to regulate gene expression in both unicellular and multicellular organisms. We focus on the advantages and disadvantages of these different tools and discuss current and future challenges in the successful translation to more complex organisms.

Self-association of amyloidogenic proteins is the main pathological trigger in a wide variety of neurodegenerative disorders. These aggregates are deposited inside or outside the cell due to hereditary mutations, environmental exposures or even normal aging. Cumulative evidence indicates that the heat shock chaperone Hsp70 possesses robust neuroprotection against various intracellular amyloids in Drosophila and mouse models. However, its protective role against extracellular amyloids was largely unknown as its presence outside the cells is very limited. Our recent manuscript in PNAS revealed that an engineered form of secreted Hsp70 (secHsp70) is highly protective against toxicity induced by extracellular deposition of the amyloid-β42 (Aβ42) peptide. In this Extra View article, we extend our analysis to other members of the heat shock protein family. We created PhiC31-based transgenic lines for human Hsp27, Hsp40, Hsp60 and Hsp70 and compared their activities in parallel against extracellular Aβ42. Strikingly, only secreted Hsp70 exhibits robust protection against Aβ42-triggered toxicity in the extracellular milieu. These observations indicate that the ability of secHsp70 to suppress Aβ42 insults is quite unique and suggest that targeted secretion of Hsp70 may represent a new therapeutic approach against Aβ42 and other extracellular amyloids. The potential applications of this engineered chaperone are discussed.

An attractive therapeutic strategy to treat Alzheimer’s Disease is to halt the accumulation of amyloid plaques by decreasing the production of Aβ1-42. A class of compounds called γ-secretase modulators (GSMs) shift the γ-secretase cleavage site of amyloid precursor protein resulting in a selective decreased production of amyloid beta (Aβ) peptide 1-42 and a concomitant increased production of the shorter Aβ peptides, Aβ1-37, Aβ1-38 and Aβ1-39. However, the biological significance of these peptides is still unclear. Our initial studies with transgenic mouse models suggest that one such short peptide, Aβ1-40, is a robust inhibitor of Aβ1-42 deposition in vivo. The last two hydrophobic residues at the C-terminal of Aβ1-42 are proposed to be critical for its enhanced rate of nucleation. Therefore we hypothesize that shorter Aβ peptides are anti-amyloidogenic and modify the toxicity of Aβ42 in vivo. In this study we examined the effect of Aβ38, expressed using our BRI2 fusion strategy, in an APP mouse model and investigated the role of shorter Aβ peptides, Aβ1-36, Aβ1-37, Aβ1-38, Aβ1-39, Aβ1-40, Aβ1-42 and Aβ1-43, by generating transgenic Drosophila melanogaster. The Aβ peptides were expressed independently or co-expressed with Aβ1-42 specifically in the eye to assess phenotype and the neurons to evaluate behavioral function. Overexpression of the shorter Aβ peptides, Aβ1-36, Aβ1-37, Aβ1-38 and Aβ1-39, was not toxic in the eye. Overexpression of Aβ1-42 resulted in a degenerative eye phenotype while expression of Aβ1-40 or Aβ1-43 had a slight effect on eye phenotype. Importantly, in flies co-expressing Aβ1-42 and the shorter Aβ peptides, Aβ1-36, Aβ1-37, Aβ1-38 and Aβ1-39, the degenerative phenotype and behavioral function was improved. These studies validate γ-secretase modulation as a clinical strategy by characterizing the attenuating effect of shorter Aβ peptides.

Significance Heat shock protein 70 (Hsp70) is a critical protein with many protective activities inside the cell. We demonstrate that forced secretion of Hsp70 is beneficial against the extracellular protein aggregates typical of Alzheimer’s disease (AD). Engineering Hsp70 enables its interaction with the amyloid-β42 peptide, the main pathogenic agent in AD. This interaction suppresses amyloid-β toxicity in the eye, reduces cell death in brain neurons, and protects neuronal architecture and function. Interestingly, secreted Hsp70 exerts this protective activity without utilizing its refolding activity and without decreasing the levels and aggregation of amyloid-β42. These results suggest a protective mechanism mediated by direct binding to amyloid-β42, which blocks amyloid-β42 neurotoxicity. We discuss here the potential therapeutic benefits of secreted Hsp70.

Protein quality control is an essential process for cellular survival. When protein damage occurs, a series of coordinated response mechanisms repair or degrade damaged proteins to avoid the accumulation of toxic protein aggregates and restore proteostasis. However, the amount of misfolded proteins increases during aging overwhelming the mechanisms responsible for protein quality control, thus leading to the development of several age-dependent neurodegenerative disorders. Interestingly, targeted expression of proteins causative of these diseases in flies reproduces the pathological behaviors seen in humans. This remarkable conservation provides a valuable experimental tool to elucidate the complex mechanisms associated with the maintenance of proteostasis. In this chapter, we summarize how Drosophila has contributed to understand the roles of the heat shock response, the unfolded protein response, autophagy and the ubiquitin proteasome system in brain aging and neurodegeneration associated with protein-misfolding disorders. In addition, we describe fundamental contributions of the fly system to the design of new therapeutic strategies for these devastating disorders.

Both active and passive immunotherapy protocols decrease insoluble amyloid-ß42 (Aß42) peptide in animal models, suggesting potential therapeutic applications against the main pathological trigger in Alzheimer's disease (AD). However, recent clinical trials have reported no significant benefits from humanized anti-Aß42 antibodies. Engineered single-chain variable fragment antibodies (scFv) are much smaller and can easily penetrate the brain, but identifying the most effective scFvs in murine AD models is slow and costly. We show here that scFvs against the N- and C-terminus of Aß42 (scFv9 and scFV42.2, respectively) that decrease insoluble Aß42 in CRND mice are neuroprotective in Drosophila models of Aß42 and amyloid precursor protein neurotoxicity. Both scFv9 and scFv42.2 suppress eye toxicity, reduce cell death in brain neurons, protect the structural integrity of dendritic terminals in brain neurons and delay locomotor dysfunction. Additionally, we show for the first time that co-expression of both anti-Aß scFvs display synergistic neuroprotective activities, suggesting that combined therapies targeting distinct Aß42 epitopes can be more effective than targeting a single epitope. Overall, we demonstrate the feasibility of using Drosophila as a first step for characterizing neuroprotective anti-Aß scFvs in vivo and identifying scFv combinations with synergistic neuroprotective activities.

A promising class of drugs to treat Alzheimer's Disease are g-secretase modulators (GSMs), which shift the γ-secretase cleavage site of amyloid precursor protein resulting in a selective decreased production of the amyloid-beta (Aβ) peptide Aβ1-42 and a concomitant increased production of the shorter Aβ peptide, Aβ1-38. Although shorter Aβ peptides have been detected in the AD brain and human CSF, the biological significance of these peptides is still unclear. Our studies with transgenic mouse models suggest that one such short peptide, Aβ1-40, is a robust inhibitor of Aβ1-42 deposition in vivo. The last two hydrophobic residues at the C-terminal of Aβ1-42 are proposed to be critical for its enhanced rate of nucleation. Therefore we hypothesize that the increase in levels of shorter Aβ peptides caused by GSMs is protective and may explain the anti-amyloidogenic effects of GSMs in vivo. To investigate the role of shorter Aβ peptides we generated transgenic Drosophilaexpressing Aβ1-36, Aβ1-37, Aβ1-38, Aβ1-39, Aβ1-40, Aβ1-42 and Aβ1-43 under the GAL4-UAS system. The Aβ peptides were expressed independently or co-expressed with Aβ1-42 specifically in the eye to assess phenotype and the motor neurons to measure behavioral function. Overexpression of Aβ1-42 resulted in degenerative eye phenotype while expression of Aβ1-40 or Aβ1-43 had a slight effect on eye phenotype. Importantly, in flies co-expressing Aβ1-42 and the shorter Aβ peptides, Aβ1-36, Aβ1-37, Aβ1-38 and Aβ1-39, the degenerative eye phenotype was improved. These studies play a significant role in characterizing the attenuating effect of shorter Aβ peptides on the pathological outcome of Aβ1-42 deposition in AD by GSMs.

Alzheimer's disease (AD) is the leading cause of dementia and the most common neurodegenerative disorder. AD is mostly a sporadic disorder and its main risk factor is age, but mutations in three genes that promote the accumulation of the amyloid-β (Aβ42) peptide revealed the critical role of amyloid precursor protein (APP) processing in AD. Neurofibrillary tangles enriched in tau are the other pathological hallmark of AD, but the lack of causative tau mutations still puzzles researchers. Here, we describe the contribution of a powerful invertebrate model, the fruit fly Drosophila melanogaster, to uncover the function and pathogenesis of human APP, Aβ42, and tau. APP and tau participate in many complex cellular processes, although their main function is microtubule stabilization and the to-and-fro transport of axonal vesicles. Additionally, expression of secreted Aβ42 induces prominent neuronal death in Drosophila, a critical feature of AD, making this model a popular choice for identifying intrinsic and extrinsic factors mediating Aβ42 neurotoxicity. Overall, Drosophila has made significant contributions to better understand the complex pathology of AD, although additional insight can be expected from combining multiple transgenes, performing genome-wide loss-of-function screens, and testing anti-tau therapies alone or in combination with Aβ42.

Mutations in the alpha-synuclein (SNCA) gene cause autosomal dominant Parkinson's disease (PD). Common SNCA polymorphisms have been associated with the risk of developing PD. Abnormal expression and post-translational modification of SNCA has been found in PD-brains. In addition to a full length transcript (SNCA-140) there are three short isoforms (SNCA-98, -112, and -126) that could be prone to aggregation. The association between SNCA polymorphisms and PD could be explained through an increased expression of these alternative transcripts. Our aim was to measure the different SNCA transcripts in the substantia nigra (SN), cerebellum (CB), and occipital cortex (OC) from PD-patients (n = 9) and healthy subjects (n = 6). In addition, we determined whether two SNCA polymorphisms (SNPs rs356165 and rs11931074) were related to differences in transcript isoform expression. PD brain tissues showed higher levels of the three short transcripts in the SN, but only SNCA-112 and SNCA-98 were significantly increased in the CB of patients vs. controls (p = 0.02, p = 0.03). The genotyping of a large cohort of PD-patients and controls showed that haplotype rs356165-A+rs11931074-G had a protective effect (OR = 0.71; CI = 0.59-0.83), while the G-T haplotype increased the risk for PD (OR = 1.44; CI = 1.06-1.96). We did not find significant differences for the SNCA levels between the haplotypes. In conclusion, we found statistically significant higher levels of the SNCA-112 and SNCA-98 transcripts in the CB of PD brains, and a trend toward higher levels of the short transcript isoforms in the SN of PD brains. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

PRKN mutations have been linked to Parkinson's disease (PD). Most of the mutational screenings have focused on the coding exons. The 3′ untranslated region (UTR) could also harbor functionally relevant nucleotide changes. We performed a mutational screening of PRKN in a cohort of early-onset PD patients (n = 235) from Spain. We found 16 mutations (five new): 16 patients (7 %) carried two mutations and only one mutation was found in 28 (12 %). Patients with two mutations had significantly lower mean age (30 ± 9 years) compared to patients with one (40 ± 7) or no mutation (42 ± 7). We found a total of 15 nucleotide variants (three new) in the 3′ UTR region. The frequency of carriers of the rare rs62637702 G allele (*94A/G) was significantly lower among the patients compared to healthy controls (n = 418) (0.03 vs. 0.004; p < 0.001), suggesting a protective role for this allele. In order to investigate the basal effect of this variant, we performed luciferase assays. No different basal activity was observed between the two alleles. In conclusion, the rs62637702 polymorphism was associated with PD. This could be a surrogate marker for disease risk, in linkage disequilibrium with other non-identified functional variant.

Movement DisordersVolume 28, Issue 14 p. 2032-2033 Letter: New Observations No differential DNA methylation of PARK2 in brain of Parkinson's disease patients and healthy controls Lorena De Mena BS, Lorena De Mena BS Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, SpainSearch for more papers by this authorLucía F. Cardo BS, Lucía F. Cardo BS Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, SpainSearch for more papers by this authorEliecer Coto PhD, Eliecer Coto PhD Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, SpainSearch for more papers by this authorVictoria Alvarez PhD, Corresponding Author Victoria Alvarez PhD Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, SpainCorrespondence to: Dr. Victoria Alvarez, Genética Molecular, Hospital Central Asturias-Maternidad, 33006 Oviedo, Spain; [email protected]Search for more papers by this authorEliecer Coto PhD, Eliecer Coto PhD Department of Medicine, University of Oviedo, Oviedo, SpainSearch for more papers by this author Lorena De Mena BS, Lorena De Mena BS Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, SpainSearch for more papers by this authorLucía F. Cardo BS, Lucía F. Cardo BS Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, SpainSearch for more papers by this authorEliecer Coto PhD, Eliecer Coto PhD Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, SpainSearch for more papers by this authorVictoria Alvarez PhD, Corresponding Author Victoria Alvarez PhD Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, SpainCorrespondence to: Dr. Victoria Alvarez, Genética Molecular, Hospital Central Asturias-Maternidad, 33006 Oviedo, Spain; [email protected]Search for more papers by this authorEliecer Coto PhD, Eliecer Coto PhD Department of Medicine, University of Oviedo, Oviedo, SpainSearch for more papers by this author First published: 18 July 2013 https://doi.org/10.1002/mds.25593Citations: 13 Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998; 392: 605–608. 2Agirre X, Roman-Gomez J, Vazquez I, et al. Abnormal methylation of the common PARK2 and PACRG promoter is associated with down-regulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia. Int J Cancer 2009 6; 118: 1945–1953. 3Jowaed A, Schmitt I, Kaut O, Wullner U. Methylation regulates alpha-synuclein expression and is decreased in Parkinson's disease patients' brains. J Neurosci 2020;30: 6355–6359. 4Matsumoto L, Takuma H, Tamaoka A, et al. CpG demethylation enhances alpha-synuclein expression and affects the pathogenesis of Parkinson's disease [serial online]. PLoS One 2020; 5: e15522. 5Kaut O, Schmitt I, Wullner U. Genome-scale methylation analysis of Parkinson's disease patients' brains reveals DNA hypomethylation and increased mRNA expression of cytochrome P450 2E1. Neurogenetics 2012; 13: 87–91. 6Cai M, Tian J, Zhao GH, Luo W, Zhang BR. Study of methylation levels of parkin gene promoter in Parkinson's disease patients. Int J Neurosci 2011; 121: 497–502. Citing Literature Volume28, Issue14December 2013Pages 2032-2033 ReferencesRelatedInformation