New Avenues for Parkinson’s Disease Therapeutics: Disease-Modifying Strategies Based on the Gut Microbiota

Dieta mediterrània; Microbiota intestinal; PrebiòticsDieta mediterránea; Microbiota intestinal; PrebióticosMediterranean diet; Gut microbiota; PrebioticsParkinson’s disease (PD) is a multifactorial neurodegenerative disorder that currently affects 1% of the population over the age of 60 years, and for which no disease-modifying treatments exist. Neurodegeneration and neuropathology in different brain areas are manifested as both motor and non-motor symptoms in patients. Recent interest in the gut–brain axis has led to increasing research into the gut microbiota changes in PD patients and their impact on disease pathophysiology. As evidence is piling up on the effects of gut microbiota in disease development and progression, another front of action has opened up in relation to the potential usage of microbiota-based therapeutic strategies in treating gastrointestinal alterations and possibly also motor symptoms in PD. This review provides status on the different strategies that are in the front line (i.e., antibiotics; probiotics; prebiotics; synbiotics; dietary interventions; fecal microbiota transplantation, live biotherapeutic products), and discusses the opportunities and challenges the field of microbiome research in PD is facing.This work was supported by funds from the La Caixa Banking Foundation (Junior LeaderFellowship LCF/BQ/PR19/11700005) to A.L

Serum metabolic biomarkers for synucleinopathy conversion in isolated REM sleep behavior disorder

Neurodegeneració; Malaltia de Parkinson; Marcadors predictiusNeurodegeneración; Enfermedad de Parkinson; Marcadores predictivosNeurodegeneration; Parkinson's disease; Predictive markersIsolated rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of Lewy-type synucleinopathies (LTS), which can present either with an initial predominant parkinsonism (Parkinson’s disease (PD)) or dementia (dementia with Lewy bodies (DLB)). To provide insights into the underlying pathogenic mechanisms, the lipoprotein and protein glycosylation profile of 82 iRBD patients, collected before and/or after their conversion to an overt LTS, and 29 matched control serum samples were assessed by nuclear magnetic resonance (NMR) spectroscopy. Data were statistically analyzed to identify altered metabolites and construct predictive models. Univariant analysis detected no differences between iRBD patients with an LTS compared to controls. However, significant differences were found when the analysis distinguished between iRBD patients that manifested initially predominant parkinsonism (pre-PD) or dementia (pre-DLB). Significant differences were also found in the analysis of paired iRBD samples pre- and post-LTS diagnosis. Predictive models were built and distinguished between controls and pre-DLB patients, and between pre-DLB and pre-PD patients. This allowed a prediction of the possible future clinical outcome of iRBD patients. We provide evidence of altered lipoprotein and glycosylation profiles in subgroups of iRBD patients. Our results indicate that metabolic alterations and inflammation are involved in iRBD pathophysiology, and suggest biological differences underlying the progression of LTS in iRBD patients. Our data also indicate that profiling of serum samples by NMR may be a useful tool for identifying short-term high-risk iRBD patients for conversion to parkinsonism or dementia.The study was funded by the Fondo de Investigación Sanitaria-Instituto de Salud Carlos III (FIS-ISCIII, Spain)-European Regional Development Fund (FEDER, E.U.) (PI13/01897 to M.V.), Ministerio de Economía y Competitividad (MINECO, Spain) (SAF2015-73997-JIN to A.L. and SAF2016-77541-R to M.V.), Fundació Bancària La Caixa (Junior Leader Fellowship LCF/BQ/PR19/11700005 to A.L. and Health Research Project HR17-00513 to M.V.) and CIBERNED (to M.V. and E.T.). A.L. was the recipient of a postdoctoral contract SAF2015-73997-JIN from MINECO (Spain) with co-funding from FEDER (E.U.) and is currently funded by the Junior Leader Program from Fundació Bancària La Caixa (grant LCF/BQ/PR19/11700005). H.X. is the recipient of a Radboud University Personal Ph.D. Grant

Sex Differences in Motor and Non-Motor Symptoms among Spanish Patients with Parkinson’s Disease

Parkinson’s disease; Non-motor symptoms; SexMalaltia de Parkinson Símptomes no motors; SexeEnfermedad de Parkinson; Síntomas no motores; SexoBackground and objective: Sex plays a role in Parkinson’s disease (PD) mechanisms. We analyzed sex difference manifestations among Spanish patients with PD. Patients and Methods: PD patients who were recruited from the Spanish cohort COPPADIS from January 2016 to November 2017 were included. A cross-sectional and a two-year follow-up analysis were conducted. Univariate analyses and general linear model repeated measure were used. Results: At baseline, data from 681 PD patients (mean age 62.54 ± 8.93) fit the criteria for analysis. Of them, 410 (60.2%) were males and 271 (39.8%) females. There were no differences between the groups in mean age (62.36 ± 8.73 vs. 62.8 ± 9.24; p = 0.297) or in the time from symptoms onset (5.66 ± 4.65 vs. 5.21 ± 4.11; p = 0.259). Symptoms such as depression (p < 0.0001), fatigue (p < 0.0001), and pain (p < 0.00001) were more frequent and/or severe in females, whereas other symptoms such as hypomimia (p < 0.0001), speech problems (p < 0.0001), rigidity (p < 0.0001), and hypersexuality (p < 0.0001) were more noted in males. Women received a lower levodopa equivalent daily dose (p = 0.002). Perception of quality of life was generally worse in females (PDQ-39, p = 0.002; EUROHIS-QOL8, p = 0.009). After the two-year follow-up, the NMS burden (Non-Motor Symptoms Scale total score) increased more significantly in males (p = 0.012) but the functional capacity (Schwab and England Activities of Daily Living Scale) was more impaired in females (p = 0.001). Conclusion: The present study demonstrates that there are important sex differences in PD. Long-term prospective comparative studies are needed.COPPADIS and the present study were developed with the help of Fundación Española de Ayuda a la Investigación en Enfermedades Neurodegenerativas y/o de Origen Genético ( https://fundaciondegen.org/) and Alpha Bioresearch (www.alphabioresearch.com). Also, we received grants from the Spanish Ministry of Economy and Competitiveness [PI16/01575] co-founded by ISCIII (Concesión de subvenciones de Proyectos de Investigación en Salud de la convocatoria 2020 de la Acción Estratégica en Salud 2017–2020 por el proyecto “PROGRESIÓN NO MOTORA E IMPACTO EN LA CALIDAD DE VIDA EN LA ENFERMEDAD DE PARKINSON”) to develop a part of the COPPADIS project

Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson's disease pathogenesis

Brain tyrosinase; Neuromelanin production; Parkinson’sTirosinasa cerebral; Producció de neuromelanina; ParkinsonTirosinasa cerebral; Producción de neuromelanina; ParkinsonIn Parkinson's disease (PD) there is a selective degeneration of neuromelanin-containing neurons, especially substantia nigra dopaminergic neurons. In humans, neuromelanin accumulates with age, the latter being the main risk factor for PD. The contribution of neuromelanin to PD pathogenesis remains unknown because, unlike humans, common laboratory animals lack neuromelanin. Synthesis of peripheral melanins is mediated by tyrosinase, an enzyme also present at low levels in the brain. Here we report that overexpression of human tyrosinase in rat substantia nigra results in age-dependent production of human-like neuromelanin within nigral dopaminergic neurons, up to levels reached in elderly humans. In these animals, intracellular neuromelanin accumulation above a specific threshold is associated to an age-dependent PD phenotype, including hypokinesia, Lewy body-like formation and nigrostriatal neurodegeneration. Enhancing lysosomal proteostasis reduces intracellular neuromelanin and prevents neurodegeneration in tyrosinase-overexpressing animals. Our results suggest that intracellular neuromelanin levels may set the threshold for the initiation of PD

Study of Dyrk1a kinase in central nervous systems development: implication in mouse retina development

El gen DYRK1A es troba situat en una regió del cromosoma 21 humà que s'ha associat a alteracions en el neurodesenvolupament. Aquest treball mostra com canvis en la dosis gènica de Dyrk1A en el ratolí causen una alteració en la cel.lularitat de les capes internes de la retina i provoquen alteracions funcionals severes. A més a més, la sobreexpressió de Dyrk1A és la única responsable de les alteracions en la retina dels animals Ts65Dn, un model murí de Síndrome de Down. El control de la mort cel.lular programada és fonamental pel correcte desenvolupament del sistema nerviós central. Aquest treball demostra que la proteïna quinasa DYRK1A és un regulador negatiu de la via intrínseca d'apoptosis durant el desenvolupament de la retina. DYRK1A no afecta la proliferació o especificació de les cèl.lules progenitores, sinó que regula el nombre de cèl.lules que moren per apoptosis. La caspasa-9 és un nou substracte de DYRK1A, i la fosforilació de la caspasa al residu treonina 125 per DYRK1A protegeix les cèl.lules de la retina de la mort apoptòtica. Aquestes dades suggereixen un model en el qual una desregulació de la resposta apoptòtica en neurones en diferenciació podria participar en la neuropatologia de malalties que pesenten una alteració en la dosis gènica de DYRK1A.DYRK1A is located in a region of human chromosome 21 (HSA21) that has been associated to the neurodevelopmental impairments shown by individuals with HSA21 aneuploidies. This work shows changes in Dyrk1A gene dosage in the mouse strongly alter the cellularity in inner retina layers and results in severe functional alterations. Moreover, overexpression of Dyrk1A is solely responsible for the retina alterations shown by Ts65Dn mice, a mouse model for Down syndrome. The precise regulation of programmed cell death is critical for the normal development of the nervous system. This work demonstrates that DYRK1A protein kinase is a negative regulator of the intrinsic apoptotic pathway in the developing retina. DYRK1A does not affect the proliferation or specification of retina progenitor cells, but rather regulates the number of cells that die by apoptosis. Caspase-9 is a novel DYRK1A substrate, and the phosphorylation on caspase-9 at threonine residue 125 by DYRK1A protects retina cells from apoptotic cell death. This data suggests a model in which dysregulation of the apoptotic response in differentiating neurons participates in the neuropathology of diseases that display DYRK1A gene dosage imbalance effects