RESUMEN
Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.
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Esclerosis Amiotrófica Lateral , Cafeína , Citocromo P-450 CYP1A2 , Progresión de la Enfermedad , Polimorfismo de Nucleótido Simple , Receptor de Adenosina A2A , Humanos , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Femenino , Masculino , Persona de Mediana Edad , Anciano , Receptor de Adenosina A2A/genética , Citocromo P-450 CYP1A2/genética , Cognición/fisiología , Cognición/efectos de los fármacos , Estudios Prospectivos , Citocromo P-450 CYP1A1/genética , Receptores de Hidrocarburo de Aril/genética , Adulto , Disfunción Cognitiva/genética , Riluzol/uso terapéutico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Factores de Transcripción con Motivo Hélice-Asa-Hélice BásicoRESUMEN
BACKGROUND: Little is known about the impact of the cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) on cognition. OBJECTIVE: Our objective was to determine the frequency and severity of cognitive impairment in RFC1-positive patients and describe the pattern of deficits. METHODS: Participants underwent a comprehensive neuropsychological assessment. Volume of the cerebellum and its lobules was measured in those who underwent a 3 Tesla-magnetic resonance scan. RESULTS: Twenty-one patients underwent a complete assessment, including 71% scoring lower than the cutoff at the Montreal Cognitive assessment and 71% having a definite cerebellar cognitive affective/Schmahmann syndrome. Three patients had dementia and seven met the criteria of mild cognitive impairment. Severity of cognitive impairment did not correlate with severity of clinical manifestations. Performance at memory and visuospatial functions tests negatively correlated with the severity of cerebellar manifestations. CONCLUSION: Cognitive manifestations are frequent in RFC1-related disorders. They should be included in the phenotype and screened systematically. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Ataxia Cerebelosa , Disfunción Cognitiva , Fenotipo , Humanos , Femenino , Masculino , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Ataxia Cerebelosa/fisiopatología , Ataxia Cerebelosa/complicaciones , Persona de Mediana Edad , Anciano , Adulto , Pruebas Neuropsicológicas , Proteína de Replicación C/genética , Imagen por Resonancia Magnética , Cerebelo/diagnóstico por imagen , Cerebelo/fisiopatología , Cerebelo/patología , Enfermedades Vestibulares/fisiopatologíaRESUMEN
CANVAS caused by RFC1 biallelic expansions is a major cause of inherited sensory neuronopathy. Detection of RFC1 expansion is challenging and CANVAS can be associated with atypical features. We clinically and genetically characterized 50 patients, selected based on the presence of sensory neuronopathy confirmed by EMG. We screened RFC1 expansion by PCR, repeat-primed PCR, and Southern blotting of long-range PCR products, a newly developed method. Neuropathological characterization was performed on the brain and spinal cord of one patient. Most patients (88%) carried a biallelic (AAGGG)n expansion in RFC1. In addition to the core CANVAS phenotype (sensory neuronopathy, cerebellar syndrome and vestibular impairment), we observed chronic cough (97%), oculomotor signs (85%), motor neuron involvement (55%), dysautonomia (50%), and parkinsonism (10%). Motor neuron involvement was found for 24 of 38 patients (63.1%). First motor neuron signs, such as brisk reflexes, extensor plantar responses, and/or spasticity, were present in 29% of patients, second motor neuron signs, such as fasciculations, wasting, weakness, or a neurogenic pattern on EMG in 18%, and both in 16%. Mixed motor and sensory neuronopathy was observed in 19% of patients. Among six non-RFC1 patients, one carried a heterozygous AAGGG expansion and a pathogenic variant in GRM1. Neuropathological examination of one RFC1 patient with an enriched phenotype, including parkinsonism, dysautonomia, and cognitive decline, showed posterior column and lumbar posterior root atrophy. Degeneration of the vestibulospinal and spinocerebellar tracts was mild. We observed marked astrocytic gliosis and axonal swelling of the synapse between first and second motor neurons in the anterior horn at the lumbar level. The cerebellum showed mild depletion of Purkinje cells, with empty baskets, torpedoes, and astrogliosis characterized by a disorganization of the Bergmann's radial glia. We found neuronal loss in the vagal nucleus. The pars compacta of the substantia nigra was depleted, with widespread Lewy bodies in the locus coeruleus, substantia nigra, hippocampus, entorhinal cortex, and amygdala. We propose new guidelines for the screening of RFC1 expansion, considering different expansion motifs. Here, we developed a new method to more easily detect pathogenic RFC1 expansions. We report frequent motor neuron involvement and different neuronopathy subtypes. Parkinsonism was more prevalent in this cohort than in the general population, 10% versus the expected 1% (P < 0.001). We describe, for the first time, the spinal cord pathology in CANVAS, showing the alteration of posterior columns and roots, astrocytic gliosis and axonal swelling, suggesting motor neuron synaptic dysfunction.
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Ataxia Cerebelosa , Disautonomías Primarias , Ataxia Cerebelosa/genética , Gliosis , Humanos , Neuronas Motoras/patología , Reflejo Anormal/fisiologíaRESUMEN
BACKGROUND: Neuroferritinopathy is a rare inherited neurodegenerative disease with brain iron accumulation characterized by brain iron overload resulting in progressive movement disorders. No treatment is currently available. OBJECTIVE: We assessed conservative iron chelation with deferiprone at 30 mg/kg/day on the disease progression with controlled periods of discontinuation. METHODS: Four patients with confirmed molecular diagnosis of neuroferritinopathy were given deferiprone at different stages of disease progression and with clinical and biological monitoring to control benefit and risk. RESULTS: The four patients showed slight to high improvement. In one case, we managed to stabilize disease progression for more than 11 years. In another case, we were able to reverse symptoms after a few months of treatment. The earliest the treatment was started, the most efficient it was on disease progression. CONCLUSIONS: Conservative iron chelation should be further assessed in neuroferritinopathy. © 2022 International Parkinson and Movement Disorder Society.
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Quelantes del Hierro , Enfermedades Neurodegenerativas , Deferiprona/uso terapéutico , Progresión de la Enfermedad , Humanos , Quelantes del Hierro/uso terapéutico , Trastornos del Metabolismo del Hierro , Distrofias Neuroaxonales , Enfermedades Neurodegenerativas/tratamiento farmacológico , Piridonas/uso terapéuticoRESUMEN
BACKGROUND: Pathogenic variants in the LRRK2 gene are a common monogenic cause of Parkinson's disease. However, only seven variants have been confirmed to be pathogenic. OBJECTIVES: We identified two novel LRRK2 variants (H230R and A1440P) and performed functional testing. METHODS: We transiently expressed wild-type, the two new variants, or two known pathogenic mutants (G2019S and R1441G) in HEK-293 T cells, with or without LRRK2 kinase inhibitor treatment. We characterized the phosphorylation and kinase activity of the mutants by western blotting. Thermal shift assays were performed to determine the folding and stability of the LRRK2 proteins. RESULTS: The two variants were found in two large families and segregate with the disease. They display altered LRRK2 phosphorylation and kinase activity. CONCLUSIONS: We identified two novel LRRK2 variants which segregate with the disease. The results of functional testing lead us to propose these two variants as novel causative mutations for familial Parkinson's disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Enfermedad de Parkinson , Células HEK293 , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Mutación/genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.
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Calpaína/genética , Discapacidad Intelectual/genética , Espasticidad Muscular/genética , Mutación/genética , Atrofia Óptica/genética , Paraplejía Espástica Hereditaria/genética , Ataxias Espinocerebelosas/genética , Adulto , Edad de Inicio , Ataxia Cerebelosa/genética , Niño , Femenino , Estudios de Asociación Genética , Humanos , Discapacidad Intelectual/diagnóstico , Masculino , Espasticidad Muscular/diagnóstico , Atrofia Óptica/diagnóstico , Linaje , Fenotipo , Ataxias Espinocerebelosas/diagnóstico , Adulto JovenRESUMEN
Homozygous mutations in the progranulin gene (GRN) are associated with neuronal ceroid lipofuscinosis 11 (CLN11), a rare lysosomal-storage disorder characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age. This is a rare condition, previously reported in only four families. In contrast, heterozygous GRN mutations are a major cause of frontotemporal dementia associated with neuronal cytoplasmic TDP-43 inclusions. We identified homozygous GRN mutations in six new patients. The phenotypic spectrum is much broader than previously reported, with two remarkably distinct presentations, depending on the age of onset. A childhood/juvenile form is characterized by classical CLN11 symptoms at an early age at onset. Unexpectedly, other homozygous patients presented a distinct delayed phenotype of frontotemporal dementia and parkinsonism after 50 years; none had epilepsy or cerebellar ataxia. Another major finding of this study is that all GRN mutations may not have the same impact on progranulin protein synthesis. A hypomorphic effect of some mutations is supported by the presence of residual levels of plasma progranulin and low levels of normal transcript detected in one case with a homozygous splice-site mutation and late onset frontotemporal dementia. This is a new critical finding that must be considered in therapeutic trials based on replacement strategies. The first neuropathological study in a homozygous carrier provides new insights into the pathological mechanisms of the disease. Hallmarks of neuronal ceroid lipofuscinosis were present. The absence of TDP-43 cytoplasmic inclusions markedly differs from observations of heterozygous mutations, suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono or bi-allelic status. An intriguing observation was the loss of normal TDP-43 staining in the nucleus of some neurons, which could be the first stage of the TDP-43 pathological process preceding the formation of typical cytoplasmic inclusions. Finally, this study has important implications for genetic counselling and molecular diagnosis. Semi-dominant inheritance of GRN mutations implies that specific genetic counselling should be delivered to children and parents of CLN11 patients, as they are heterozygous carriers with a high risk of developing dementia. More broadly, this study illustrates the fact that genetic variants can lead to different phenotypes according to their mono- or bi-allelic state, which is a challenge for genetic diagnosis.
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Demencia Frontotemporal/genética , Lipofuscinosis Ceroideas Neuronales/genética , Trastornos Parkinsonianos/genética , Progranulinas/genética , Adolescente , Adulto , Edad de Inicio , Ataxia Cerebelosa/genética , Niño , Disfunción Cognitiva/genética , Epilepsia/genética , Femenino , Demencia Frontotemporal/diagnóstico por imagen , Demencia Frontotemporal/fisiopatología , Heterocigoto , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación , Lipofuscinosis Ceroideas Neuronales/diagnóstico por imagen , Lipofuscinosis Ceroideas Neuronales/fisiopatología , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/fisiopatología , Progranulinas/metabolismo , Empalme del ARN/genética , Enfermedades Raras , Retinitis Pigmentosa/genética , Proteinopatías TDP-43/diagnóstico por imagen , Proteinopatías TDP-43/genética , Proteinopatías TDP-43/fisiopatología , Adulto JovenRESUMEN
A variety of missense mutations and a stop mutation in the gene coding for transmembrane protein 240 (TMEM240) have been reported to be the causative mutations of spinocerebellar ataxia 21 (SCA21). We aimed to investigate the expression of TMEM240 protein in mouse brain at the tissue, cellular, and subcellular levels. Immunofluorescence labeling showed TMEM240 to be expressed in various areas of the brain, with the highest levels in the hippocampus, isocortex, and cerebellum. In the cerebellum, TMEM240 was detected in the deep nuclei and the cerebellar cortex. The protein was expressed in all three layers of the cortex and various cerebellar neurons. TMEM240 was localized to climbing, mossy, and parallel fiber afferents projecting to Purkinje cells, as shown by co-immunostaining with VGLUT1 and VGLUT2. Co-immunostaining with synaptophysin, post-synaptic fractionation, and confirmatory electron microscopy showed TMEM240 to be localized to the post-synaptic side of synapses near the Purkinje-cell soma. Similar results were obtained in human cerebellar sections. These data suggest that TMEM240 may be involved in the organization of the cerebellar network, particularly in synaptic inputs converging on Purkinje cells. This study is the first to describe TMEM240 expression in the normal mouse brain.
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Proteínas de la Membrana/biosíntesis , Mutación/fisiología , Terminales Presinápticos/metabolismo , Células de Purkinje/metabolismo , Degeneraciones Espinocerebelosas/metabolismo , Adulto , Anciano , Animales , Cerebelo/metabolismo , Cerebelo/patología , Expresión Génica , Humanos , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Terminales Presinápticos/ultraestructura , Células de Purkinje/ultraestructura , Degeneraciones Espinocerebelosas/genética , Degeneraciones Espinocerebelosas/patología , Adulto JovenRESUMEN
Accumulating data support the role of tau pathology in cognitive decline in ageing and Alzheimer's disease, but underlying mechanisms remain ill-defined. Interestingly, ageing and Alzheimer's disease have been associated with an abnormal upregulation of adenosine A2A receptor (A2AR), a fine tuner of synaptic plasticity. However, the link between A2AR signalling and tau pathology has remained largely unexplored. In the present study, we report for the first time a significant upregulation of A2AR in patients suffering from frontotemporal lobar degeneration with the MAPT P301L mutation. To model these alterations, we induced neuronal A2AR upregulation in a tauopathy mouse model (THY-Tau22) using a new conditional strain allowing forebrain overexpression of the receptor. We found that neuronal A2AR upregulation increases tau hyperphosphorylation, potentiating the onset of tau-induced memory deficits. This detrimental effect was linked to a singular microglial signature as revealed by RNA sequencing analysis. In particular, we found that A2AR overexpression in THY-Tau22 mice led to the hippocampal upregulation of C1q complement protein-also observed in patients with frontotemporal lobar degeneration-and correlated with the loss of glutamatergic synapses, likely underlying the observed memory deficits. These data reveal a key impact of overactive neuronal A2AR in the onset of synaptic loss in tauopathies, paving the way for new therapeutic approaches.
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Complemento C1q/metabolismo , Neuronas/metabolismo , Receptor de Adenosina A2A/genética , Receptor de Adenosina A2A/metabolismo , Sinapsis/patología , Tauopatías/genética , Tauopatías/patología , Animales , Autopsia , Degeneración Lobar Frontotemporal/genética , Degeneración Lobar Frontotemporal/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Trastornos de la Memoria/etiología , Trastornos de la Memoria/psicología , Ratones , Ratones Transgénicos , Mutación , Aprendizaje Espacial , Tauopatías/psicología , Proteínas tau/genéticaRESUMEN
BACKGROUND: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease causing parkinsonian symptoms. Altered DNA methylation of the microtubule-associated protein tau gene correlates with the expression changes in Alzheimer's disease and Parkinson's disease brains. However, few studies examine the sequences beyond the constitutive promoter. OBJECTIVES: Because activating different microtubule-associated protein tau gene control regions via methylation might regulate the differential tau expression constituting the specific signatures of individual tauopathies, we compared methylation of a candidate promoter, intron 0. METHODS: We assessed DNA methylation in the brains of patients with different tauopathies (35 Alzheimer's disease, 10 corticobasal degeneration, and 18 PSP) and 19 controls by intron 0 pyrosequencing. We also evaluated methylation in an independent cohort of 11 PSP cases and 12 controls. Frontal (affected by tau pathology) and occipital (unaffected) cortices were analyzed. RESULTS: In the initial samples, one CpG island site in intron 0 (CpG1) showed significant hypomethylation in PSP-affected frontal cortices when compared with controls (P = .022). Such hypomethylation was observed in replicate samples, but not in occipital cortices or other tauopathies. PSP and control samples (combining the initial and replicate samples) remained significantly different after adjustment for potential confounding factors (age, H1/H1 diplotype; P = .0005). PSP-affected tissues exhibited microtubule-associated protein tau RNA hyperexpression when compared with controls (P = .004), although no correlation with CpG1 methylation was observed. CONCLUSIONS: This exploratory study suggests that regions other than the constitutive promoter may be involved in microtubule-associated protein tau gene regulation in tauopathies and that intron 0 hypomethylation may be a specific epigenetic signature of PSP. These preliminary findings require confirmation. © 2016 International Parkinson and Movement Disorder Society.
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Lóbulo Frontal/metabolismo , Lóbulo Occipital/metabolismo , Parálisis Supranuclear Progresiva/metabolismo , Bancos de Tejidos , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Islas de CpG , Metilación de ADN , Femenino , Humanos , Intrones , Masculino , Persona de Mediana Edad , Regiones Promotoras GenéticasRESUMEN
Autosomal dominant cerebellar ataxia corresponds to a clinically and genetically heterogeneous group of neurodegenerative disorders that primarily affect the cerebellum. Here, we report the identification of the causative gene in spinocerebellar ataxia 21, an autosomal-dominant disorder previously mapped to chromosome 7p21.3-p15.1. This ataxia was firstly characterized in a large French family with slowly progressive cerebellar ataxia, accompanied by severe cognitive impairment and mental retardation in two young children. Following the recruitment of 12 additional young family members, linkage analysis enabled us to definitively map the disease locus to chromosome 1p36.33-p36.32. The causative mutation, (c.509C>T/p.P170L) in the transmembrane protein gene TMEM240, was identified by whole exome sequencing and then was confirmed by Sanger sequencing and co-segregation analyses. Index cases from 368 French families with autosomal-dominant cerebellar ataxia were also screened for mutations. In seven cases, we identified a range of missense mutations (c.509C>T/p.P170L, c.239C>T/p.T80M, c.346C>T/p.R116C, c.445G>A/p.E149K, c.511C>T/p.R171W), and a stop mutation (c.489C>G/p.Y163*) in the same gene. TMEM240 is a small, strongly conserved transmembrane protein of unknown function present in cerebellum and brain. Spinocerebellar ataxia 21 may be a particular early-onset disease associated with severe cognitive impairment.
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Trastornos del Conocimiento/genética , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Mutación/fisiología , Degeneraciones Espinocerebelosas/genética , Adolescente , Edad de Inicio , Secuencia de Aminoácidos , Niño , Preescolar , Cromosomas Humanos Par 1/genética , Trastornos del Conocimiento/psicología , Estudios de Cohortes , Secuencia Conservada , Análisis Mutacional de ADN , Exoma/genética , Femenino , Francia , Ligamiento Genético , Humanos , Lactante , Discapacidad Intelectual/psicología , Pruebas de Inteligencia , Intrones , Masculino , Proteínas de la Membrana/fisiología , Datos de Secuencia Molecular , Pruebas Neuropsicológicas , Linaje , Reacción en Cadena de la Polimerasa , Degeneraciones Espinocerebelosas/patología , Degeneraciones Espinocerebelosas/psicología , Adulto JovenRESUMEN
INTRODUCTION: Spastic paraplegia (SPG) is a heterogenous group of neurodegenerative disorders, that may include ocular involvement. Here we report the clinical data of a patient with late-onset Kjellin syndrome, a peculiar form of hereditary SPG with macular dystrophy. MATERIALS AND METHODS: Clinical, functional and multimodal retinal imaging data were collected. Genetic testing was performed by Whole Exome Sequencing (WES). RESULTS: A 52-year-old female patient with SPG of unknown origin was referred for a progressive visual acuity loss. Multimodal fundus imaging revealed a peculiar macular dystrophy. Given the specific association of macular dystrophy and SPG, a Kjellin syndrome was suspected and genetic testing performed. WES revealed biallelic pathogenic variants in SPG11, co-segregating with disease in the family. CONCLUSION: Careful ophthalmological examination prompted the diagnosis and guided molecular testing. This case underlines the importance of a neuro-ophthalmologic assessment in patients with SPG.
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Fondo de Ojo , Paraplejía Espástica Hereditaria , Tomografía de Coherencia Óptica , Humanos , Femenino , Persona de Mediana Edad , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/diagnóstico , Agudeza Visual/fisiología , Angiografía con Fluoresceína/métodos , Proteínas/genética , Degeneración Macular/genética , Degeneración Macular/diagnóstico , Linaje , Secuenciación del Exoma , Mutación , Imagen MultimodalRESUMEN
ApoE4 is a major genetic risk determinant for Alzheimer's disease (AD) and drives its pathogenesis via Aß-dependent and -independent pathways. C/EBPß, a proinflammatory cytokine-activated transcription factor, is upregulated in AD patients and increases cytokines and δ-secretase expression. Under physiological conditions, ApoE is mainly expressed in glial cells, but its neuronal expression is highly elevated under pathological stresses. However, how neuronal ApoE4 mediates AD pathologies remains incompletely understood. Here we show that ApoE4 activates C/EBPß that subsequently regulates APP, Tau and BACE1 mRNA expression in mouse neurons, driving AD-like pathogenesis. To interrogate the pathological roles of both human ApoE4 and C/EBPß elevation in neurons in the aged brain, we develop neuronal specific Thy1-ApoE4/C/EBPß double transgenic mice. Neuronal ApoE4 strongly activates C/EBPß and augmented δ-secretase subsequently cleaves increased mouse APP and Tau, promoting AD-like pathologies. Notably, Thy1-ApoE4/C/EBPß mice develop amyloid deposits, Tau aggregates and neurodegeneration in an age-dependent manner, leading to synaptic dysfunction and cognitive disorders. Thus, our findings demonstrate that neuronal ApoE4 triggers AD pathogenesis via activating the crucial regulator C/EBPß.
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Enfermedad de Alzheimer , Apolipoproteína E4 , Proteína beta Potenciadora de Unión a CCAAT , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Apolipoproteína E4/genética , Ácido Aspártico Endopeptidasas , Proteína beta Potenciadora de Unión a CCAAT/genética , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Humanos , Ratones , Neuronas/metabolismoRESUMEN
Tau pathology is instrumental in the gradual loss of neuronal functions and cognitive decline in tauopathies, including Alzheimer's disease (AD). Earlier reports showed that adenosine metabolism is abnormal in the brain of AD patients while consequences remained ill-defined. Herein, we aimed at investigating whether manipulation of adenosine tone would impact Tau pathology, associated molecular alterations and subsequent neurodegeneration. We demonstrated that treatment with an inhibitor (J4) of equilibrative nucleoside transporter 1 (ENT1) exerted beneficial effects in a mouse model of Tauopathy. Treatment with J4 not only reduced Tau hyperphosphorylation but also rescued memory deficits, mitochondrial dysfunction, synaptic loss, and abnormal expression of immune-related gene signatures. These beneficial effects were particularly ascribed to the ability of J4 to suppress the overactivation of AMPK (an energy reduction sensor), suggesting that normalization of energy dysfunction mitigates neuronal dysfunctions in Tauopathy. Collectively, these data highlight that targeting adenosine metabolism is a novel strategy for tauopathies.
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Encéfalo/efectos de los fármacos , Encéfalo/patología , Tranportador Equilibrativo 1 de Nucleósido/antagonistas & inhibidores , Tauopatías/metabolismo , Tauopatías/patología , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Humanos , RatonesRESUMEN
Alzheimer's disease is the most common form of dementia characterized by intracellular aggregates of hyperphosphorylated Tau protein and extracellular accumulation of amyloid ß (Aß) peptides. We previously demonstrated that the purinergic receptor P2X7 (P2X7) plays a major role in Aß-mediated neurodegeneration but the relationship between P2X7 and Tau remained overlooked. Such a link was supported by cortical upregulation of P2X7 in patients with various type of frontotemporal lobar degeneration, including mutation in the Tau-coding gene, MAPT, as well as in the brain of a Tauopathy mouse model (THY-Tau22). Subsequent phenotype analysis of P2X7-deficient Tau mice revealed the instrumental impact of this purinergic receptor. Indeed, while P2X7-deficiency had a moderate effect on Tau pathology itself, we observed a significant reduction of microglia activation and of Tau-related inflammatory mediators, particularly CCL4. Importantly, P2X7 deletion ultimately rescued synaptic plasticity and memory impairments of Tau mice. Altogether, the present data support a contributory role of P2X7 dysregulation on processes governing Tau-induced brain anomalies. Due to the convergent role of P2X7 blockade in both Aß and Tau background, P2X7 inhibitors might prove to be ideal candidate drugs to curb the devastating cognitive decline in Alzheimer's disease and Tauopathies.
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Enfermedad de Alzheimer , Receptores Purinérgicos P2X7/deficiencia , Tauopatías , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides , Animales , Cognición , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Tauopatías/genética , Proteínas tau/genéticaRESUMEN
INTRODUCTION: A phenotype of isolated parkinsonism mimicking Idiopathic Parkinson's Disease (IPD) is a rare clinical presentation of GRN and C9orf72 mutations, the major genetic causes of frontotemporal dementia (FTD). It still remains controversial if this association is fortuitous or not, and which clinical clues could reliably suggest a genetic FTD etiology in IPD patients. This study aims to describe the clinical characteristics of FTD mutation carriers presenting with IPD phenotype, provide neuropathological evidence of the mutation's causality, and specifically address their "red flags" according to current IPD criteria. METHODS: Seven GRN and C9orf72 carriers with isolated parkinsonism at onset, and three patients from the literature were included in this study. To allow better delineation of their phenotype, the presence of supportive, exclusion and "red flag" features from MDS criteria were analyzed for each case. RESULTS: Amongst the ten patients (5 GRN, 5 C9orf72), seven fulfilled probable IPD criteria during all the disease course, while behavioral/language or motoneuron dysfunctions occurred later in three. Disease duration was longer and dopa-responsiveness was more sustained in C9orf72 than in GRN carriers. Subtle motor features, cognitive/behavioral changes, family history of dementia/ALS were suggestive clues for a genetic diagnosis. Importantly, neuropathological examination in one patient revealed typical TDP-43-inclusions without alpha-synucleinopathy, thus demonstrating the causal link between FTD mutations, TDP-43-pathology and PD phenotype. CONCLUSION: We showed that, altogether, family history of early-onset dementia/ALS, the presence of cognitive/behavioral dysfunction and subtle motor characteristics are atypical features frequently present in the parkinsonian presentations of GRN and C9orf72 mutations.