RESUMEN
BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Atrofia de Múltiples Sistemas , Atrofias Olivopontocerebelosas , Degeneración Estriatonigral , Autoanticuerpos , Autopsia , Estudio de Asociación del Genoma Completo , Humanos , Atrofia de Múltiples Sistemas/genética , Atrofia de Múltiples Sistemas/patología , Proteínas del Tejido Nervioso/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , alfa-Sinucleína/metabolismoRESUMEN
BACKGROUND: Essential tremor and Parkinson's syndrome are two common movement disorders that may co-occur in some individuals. There is no diagnostic neuropathology for essential tremor, but in PD and other Parkinson's syndrome variants, the neuropathology is well known. The spectrum of Parkinson's syndrome variants associated with essential tremor, their clinical features, and course have not been determined in autopsy-confirmed cases. OBJECTIVES: To identify: diagnostic features of essential tremor/Parkinson's syndrome, different Parkinson's syndrome variants, and long-term clinical profile in such cases. METHODS: Patients that had an essential tremor diagnosis and a subsequent clinical or pathological diagnosis of Parkinson's syndrome seen in our clinic during 50 years were included. The diagnosis of parkinsonism was made when bradykinesia, rigidity, and resting tremor were all clinically evident. RESULTS: Twenty-one cases were included. All the common variants of parkinsonism co-occurred with essential tremor. The most common was PD (67%) followed by PSP. The pathological findings were not predicted clinically in 2 cases that had essential tremor/PD and in all 5 essential tremor/PSP cases. CONCLUSION: In most essential tremor/Parkinson's syndrome patients, the main motor features of parkinsonism-bradykinesia, rigidity, and resting tremor-were identifiable. All known degenerative Parkinson's syndrome variants co-occurred in essential tremor patients. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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Temblor Esencial/terapia , Enfermedad de Parkinson/complicaciones , Trastornos Parkinsonianos/complicaciones , Temblor/complicaciones , Edad de Inicio , Temblor Esencial/complicaciones , Temblor Esencial/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/fisiopatología , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/fisiopatologíaRESUMEN
Biallelic DNAJC12 mutations were described in children with hyperphenylalaninemia, neurodevelopmental delay, and dystonia. We identified DNAJC12 homozygous null variants (c.187A>T;p.K63* and c.79-2A>G;p.V27Wfs*14) in two kindreds with early-onset parkinsonism. Both probands had mild intellectual disability, mild nonprogressive, motor symptoms, sustained benefit from small dose of levodopa, and substantial worsening of symptoms after levodopa discontinuation. Neuropathology (Proband-A) revealed no alpha-synuclein pathology, and substantia nigra depigmentation with moderate cell loss. DNAJC12 transcripts were reduced in both patients. Our results suggest that DNAJC12 mutations (absent in 500 early-onset patients with Parkinson's disease) rarely cause dopa-responsive nonprogressive parkinsonism in adulthood, but broaden the clinical spectrum of DNAJC12 deficiency. Ann Neurol 2017;82:640-646.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Levodopa/uso terapéutico , Mutación/genética , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/genética , Proteínas Represoras/genética , Adulto , Péptidos beta-Amiloides/metabolismo , Aminas Biogénicas/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Análisis Mutacional de ADN , Proteínas de Unión al ADN/metabolismo , Salud de la Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Parkinsonianos/patología , Fenilalanina/metabolismo , Proteína Sequestosoma-1/metabolismo , Adulto Joven , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismoRESUMEN
In the human brain, the claustrum is a small subcortical telencephalic nucleus, situated between the insular cortex and the putamen. A plethora of neuroanatomical studies have shown the existence of dense, widespread, bidirectional and bilateral monosynaptic interconnections between the claustrum and most cortical areas. A rapidly growing body of experimental evidence points to the integrative role of claustrum in complex brain functions, from motor to cognitive. Here, we examined for the first time, the behaviour of the classical monoamine neurotransmitters dopamine, noradrenaline and serotonin in the claustrum of the normal autopsied human brain and of patients who died with idiopathic Parkinson's disease (PD). We found in the normal claustrum substantial amounts of all three monoamine neurotransmitters, substantiating the existence of the respective brain stem afferents to the claustrum. In PD, the levels of dopamine and noradrenaline were greatly reduced by 93 and 81%, respectively. Serotonin levels remained unchanged. We propose that by virtue of their projections to the claustrum, the brain stem dopamine, noradrenaline and serotonin systems interact directly with the cortico-claustro-cortical information processing mechanisms, by-passing their (parallel) routes via the basal ganglia-thalamo-cortical circuits. We suggest that loss of dopamine and noradrenaline in the PD claustrum is critical in the aetiology of both the motor and the non-motor symptoms of PD.
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Ganglios Basales/metabolismo , Dopamina/metabolismo , Norepinefrina/metabolismo , Enfermedad de Parkinson/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Corteza Cerebral/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatología , Serotonina/metabolismoRESUMEN
We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
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Temblor Esencial/genética , Estudio de Asociación del Genoma Completo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Proteínas Serina-Treonina Quinasas/genética , alfa Catenina/genética , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal-dominant trait, which could not be ascribed to any known mutation. DNA from three affected members was subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically matched controls. Subsequent genotyping was performed in a multi-ethnic case-control series consisting of 2928 patients and 2676 control subjects from Canada, Norway, Taiwan, Tunisia, and the USA. A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation, of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch-German-Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows that the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions. In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor-sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2 and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology.
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Cuerpos de Lewy/genética , Chaperonas Moleculares/genética , Mutación/genética , Enfermedad de Parkinson/genética , Adulto , Edad de Inicio , Anciano , Secuencia de Bases , Estudios de Casos y Controles , Células Cultivadas , Endocitosis/genética , Endosomas/genética , Familia , Femenino , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Enfermedad por Cuerpos de Lewy/genética , Masculino , Persona de Mediana Edad , Chaperonas Moleculares/inmunología , Linaje , Proteínas Serina-Treonina Quinasas/genética , Alineación de Secuencia , Análisis de Secuencia de ADN , Proteínas de Transporte Vesicular/genéticaRESUMEN
BACKGROUND: Drug-induced parkinsonism is a well-known complication of several different drugs--the most common being neuroleptic-induced parkinsonism. However, very few autopsies have been reported in such cases. METHODS: Patients assessed at Movement Disorders Clinic Saskatchewan are offered brain autopsy. Detailed clinical records are kept. RESULTS: Brains were obtained from 7 drug-induced parkinsonism patients with parkinsonian symptom onset coinciding with use of drugs known to produce parkinsonism. Six were on antipsychotics and 1 was on metoclopramide. Three cases were treated with levodopa for parkinsonism. In two cases, parkinsonian features reversed after stopping the offending agent. Both had autopsy evidence of preclinical PD. In 4 of the remaining 5, dopamine-blocking drugs were continued until death. In 4 of those 5, brain histology revealed no cause for the parkinsonism, but 1 had mild SN neuronal loss without Lewy bodies. CONCLUSION: This study shows that reversal of parkinsonism after discontinuing offending drugs does not indicate absence of underlying pathology. Neuroleptics can unmask preclinical PD in patients with insufficient SN damage for the disease to manifest clinically. Though the mechanism of sustained parkinsonian features after discontinuing neuroleptics remains to be established, it is unlikely that dopamine receptor block leads to retrograde SN neuronal degeneration. Furthermore, L-dopa does not appear to be toxic to SN.
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Enfermedad de Parkinson Secundaria/patología , Sustancia Negra/patología , Anciano , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Dopaminérgicos/efectos adversos , Dopaminérgicos/uso terapéutico , Humanos , Levodopa/efectos adversos , Levodopa/uso terapéutico , Cuerpos de Lewy/patología , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson Secundaria/inducido químicamenteRESUMEN
BACKGROUND: Several studies have compared early-onset Parkinson disease (EOPD) and late-onset Parkinson disease (LOPD) but most are not based on autopsy confirmed cases. METHODS: We compared clinical and pharmacological profiles, time to reach irreversible Hoehn and Yahr (H&Y) Stage 3 and levodopa motor complications in autopsy confirmed EOPD and LOPD cases. RESULTS: At first clinic visit EOPD cases were younger but had longer disease duration and they died at a younger age (all p<0.0001). Anti-Parkinsonian drug use, including levodopa, was significantly delayed in EOPD. Lifetime use of amantadine (p<0.05) and dopamine agonists (p<0.01) were higher in EOPD. While lifetime use of levodopa was similar in the two groups, levodopa was used for a significantly longer period by EOPD (p< 0.0001). EOPD had a higher cumulative incidence of dyskinesias (p<0.01), wearing-off (p<0.01), and on-off (p<0.01). However, the time to dyskinesia onset was similar in the two groups. The threshold to wearing-off was much longer in EOPD (p<0.01). H&Y stage profile at first visit was similar in the two groups. The duration from disease onset to reach irreversible H&Y stage 3 was significantly longer in EOPD. CONCLUSIONS: Our observations indicate that progression of PD is slower in EOPD and suggest that the pre-clinical interval in this group is longer. These findings can be used for case selection for drug trials and studies of the pathogenesis of PD.
Asunto(s)
Progresión de la Enfermedad , Discinesias/fisiopatología , Enfermedad de Parkinson/fisiopatología , Adulto , Factores de Edad , Edad de Inicio , Anciano , Anciano de 80 o más Años , Antiparkinsonianos , Discinesias/tratamiento farmacológico , Discinesias/epidemiología , Discinesias/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/epidemiología , Índice de Severidad de la EnfermedadRESUMEN
The cause of degeneration of nigrostriatal dopamine (DA) neurons in idiopathic Parkinson's disease (PD) is still unknown. Intraneuronally, DA is largely confined to synaptic vesicles where it is protected from metabolic breakdown. In the cytoplasm, however, free DA can give rise to formation of cytotoxic free radicals. Normally, the concentration of cytoplasmic DA is kept at a minimum by continuous pumping activity of the vesicular monoamine transporter (VMAT)2. Defects in handling of cytosolic DA by VMAT2 increase levels of DA-generated oxy radicals ultimately resulting in degeneration of DAergic neurons. Here, we isolated for the first time, DA storage vesicles from the striatum of six autopsied brains of PD patients and four controls and measured several indices of vesicular DA storage mechanisms. We found that (1) vesicular uptake of DA and binding of the VMAT2-selective label [(3)H]dihydrotetrabenazine were profoundly reduced in PD by 87-90% and 71-80%, respectively; (2) after correcting for DA nerve terminal loss, DA uptake per VMAT2 transport site was significantly reduced in PD caudate and putamen by 53 and 55%, respectively; (3) the VMAT2 transport defect appeared specific for PD as it was not present in Macaca fascicularis (7 MPTP and 8 controls) with similar degree of MPTP-induced nigrostriatal neurodegeneration; and (4) DA efflux studies and measurements of acidification in the vesicular preparations suggest that the DA storage impairment was localized at the VMAT2 protein itself. We propose that this VMAT2 defect may be an early abnormality promoting mechanisms leading to nigrostriatal DA neuron death in PD.
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Cuerpo Estriado/ultraestructura , Dopamina/metabolismo , Enfermedad de Parkinson/patología , Vesículas Sinápticas/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Inhibidores de Captación de Dopamina/farmacocinética , Femenino , Ácido Homovanílico/metabolismo , Humanos , Intoxicación por MPTP/patología , Macaca fascicularis , Masculino , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacocinética , Tritio/metabolismo , Tritio/farmacocinéticaRESUMEN
The accumulation of insoluble amyloid-beta (Aß) peptides is associated with neurodegenerative disorders, such as Alzheimer's disease (AD). As essential tremor (ET) could involve neurodegenerative processes in the cerebellum, we quantified soluble and insoluble Aß in cerebellar cortices from patients diagnosed with ET (n=9), compared to Controls (n=16) or individuals with Parkinson's disease (n=10). Although ante-mortem cognitive performance was not documented, all individuals included had the diagnosis of AD ruled out by a neuropathologist. ELISA-determined concentrations of insoluble Aß42 in ET patients displayed a bimodal distribution, with a median 246-fold higher than in Controls (P<0.01, Kruskal-Wallis). Higher Aß42 concentrations were measured in the parietal cortex of the same ET patients, compared to Controls (107-fold median increase, P<0.01, Kruskal-Wallis), but similar phosphorylated tau levels were detected. The rise in cerebellar insoluble Aß42 concentrations is not associated to APP expression and processing or the ApoE4 status. However, Aß42 levels in ET individuals were correlated with cerebellar insoluble phosphorylated tau (r(2)=0.71, P=0.005), unphosphorylated neurofilament heavy chain (NF-H; r(2)=0.50, P=0.030) and Lingo-1 (r(2)=0.73, P=0.007), indicative of a generalized neurodegenerative process involving the cerebellum. Our results suggest prevalent accumulations of insoluble Aß42 in the cerebellum of ET, but not in age-matched PD. Whether this anomaly plays a role in ET symptoms warrants further investigations.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Corteza Cerebelosa/metabolismo , Temblor Esencial/metabolismo , Fragmentos de Péptidos/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Apolipoproteína E4/metabolismo , Femenino , Humanos , Masculino , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Neurofilamentos/metabolismo , Lóbulo Parietal/metabolismo , Enfermedad de Parkinson/metabolismo , Fosforilación , Células de Purkinje/metabolismo , Lóbulo Temporal/metabolismo , Proteínas tau/metabolismoRESUMEN
BACKGROUND: A novel mutation (p.N855S) in DNAJC13 has been linked to familial, late-onset Lewy body parkinsonism in a Dutch-German-Russian Mennonite multi-incident kindred. METHODS: DNAJC13 was sequenced in 201 patients with parkinsonism and 194 controls from Canada. Rare (minor allele frequency < 0.01) missense variants identified in patients were genotyped in two Parkinson's disease case-controls cohorts. RESULTS: Eighteen rare missense mutations were identified; four were observed in controls, three were observed in both patients and controls, and eleven were identified only in patients. Subsequent genotyping showed p.E1740Q and p.L2170W to be more frequent in patients, and p.R1516H being more frequent in controls. Additionally, p.P336A, p.V722L, p.N855S, p.R1266Q were seen in one patient each, and p.T1895M was found in two patients. CONCLUSION: Although the contribution of rare genetic variation in DNAJC13 to parkinsonisms remains to be further elucidated, this study suggests that, in addition to p.N855S, other rare variants might affect disease susceptibility.
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Predisposición Genética a la Enfermedad , Chaperonas Moleculares/genética , Mutación Missense/genética , Enfermedad de Parkinson/genética , Trastornos Parkinsonianos/genética , Edad de Inicio , Femenino , Frecuencia de los Genes/genética , Genotipo , Humanos , Masculino , Enfermedad de Parkinson/diagnóstico , Trastornos Parkinsonianos/diagnósticoRESUMEN
BACKGROUND: A pathogenic mutation (VPS35 p.D620N) within the retromer complex has been shown to segregate with late-onset Parkinson's disease (PD). Several studies have subsequently detected the mutation in patients with PD and not in controls. METHODS: Mutation screening of the coding regions of the retromer cargo recognition complex genes (VPS26A/B, VPS29, and VPS35) was carried out in patients with PD (n = 396), atypical parkinsonism (n = 229), and in 368 controls. RESULTS: Overall, we identified five rare nonsynonymous mutations in VPS26A and one in VPS35; none were observed in VPS26B or VPS29. Three VPS26A variants (p.K93E, p.M112V, and p.K297X), identified in patients with atypical parkinsonism, were not observed in controls from this study (n = 368) or from publically available data sets (n = 4,426). CONCLUSION: Our results support the hypothesis that rare variants in the retromer complex genes may be involved in the development of parkinsonism, although further studies are warranted before any solid conclusions can be drawn.
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Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Trastornos Parkinsonianos/genética , Proteínas de Transporte Vesicular/genética , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Femenino , Humanos , Cooperación Internacional , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
We review the Saskatchewan Movement Disorders Program, which started in 1968 and has had the dual goals of patient care and research. The clinics are structured to collect research-worthy data including videos, longitudinal follow-up, and autopsy studies of patients seen in the clinics. At every clinic visit, the patient is evaluated by one or both authors. A total of 25% to 30% of the deceased come to autopsy. Frozen half-brain and formalin-fixed remnants from autopsy are preserved in our laboratories. Patients not seen in our clinic are not included in research, which makes it different from brain banks. So far, 515 cases have come to autopsy. So far, there have been 17 collaborating scientific teams from Canada, the United States, Europe, and Japan. The collaborators are not charged for access to our resources. This program offers a unique opportunity to study multiple aspects of movement disorder patients seen in clinical practice.
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Trastornos del Movimiento/terapia , Humanos , Cooperación Internacional , Trastornos del Movimiento/patología , Trastornos del Movimiento/rehabilitación , Atención al Paciente , Investigación , SaskatchewanRESUMEN
The identification of genetic causes for Mendelian disorders has been based on the collection of multi-incident families, linkage analysis, and sequencing of genes in candidate intervals. This study describes the application of next-generation sequencing technologies to a Swiss kindred presenting with autosomal-dominant, late-onset Parkinson disease (PD). The family has tremor-predominant dopa-responsive parkinsonism with a mean onset of 50.6 ± 7.3 years. Exome analysis suggests that an aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 (VPS35 c.1858G>A; p.Asp620Asn) is the genetic determinant of disease. VPS35 is a central component of the retromer cargo-recognition complex, is critical for endosome-trans-golgi trafficking and membrane-protein recycling, and is evolutionarily highly conserved. VPS35 c.1858G>A was found in all affected members of the Swiss kindred and in three more families and one patient with sporadic PD, but it was not observed in 3,309 controls. Further sequencing of familial affected probands revealed only one other missense variant, VPS35 c.946C>T; (p.Pro316Ser), in a pedigree with one unaffected and two affected carriers, and thus the pathogenicity of this mutation remains uncertain. Retromer-mediated sorting and transport is best characterized for acid hydrolase receptors. However, the complex has many types of cargo and is involved in a diverse array of biologic pathways from developmental Wnt signaling to lysosome biogenesis. Our study implicates disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process leading to PD.
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Mutación , Enfermedad de Parkinson/genética , Proteínas de Transporte Vesicular/genética , Adulto , Edad de Inicio , Secuencia de Aminoácidos , Transporte Biológico , Endosomas/genética , Endosomas/metabolismo , Femenino , Regulación de la Expresión Génica , Variación Genética , Genoma Humano , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Vacuolas/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Red trans-Golgi/metabolismoRESUMEN
Essential tremor (ET) is the most prevalent adult-onset movement disorder. Despite its health burden, no clear pathognomonic sign has been identified to date because of the rarity of clinicopathological studies. Moreover, treatment options are still scarce and have not significantly changed in the last 30 years, underscoring the urgent need to develop new treatment avenues. In the recent years, leucine-rich repeat (LRR) and immunoglobulin (Ig) domain-containing Nogo receptor-interacting proteins 1 and 2 (LINGO1 and LINGO2, respectively) have been increasingly regarded as possible ET modulators due to emerging genetic association studies linking LINGO with ET. We have investigated LINGO protein and messenger RNA (mRNA) expression in the cerebellum of patients with ET, patients with Parkinson's disease (PD), and a control group using Western immunoblotting and in situ hybridization. Protein levels of LINGO1, but not LINGO2, were significantly increased in the cerebellar cortex of ET patients compared with controls, particularly in individuals with longer disease duration. Compared with controls, LINGO1 protein levels were increased in the cerebellar white matter of PD and ET patients but, for the latter, only when disease duration exceeded 20 years. However, no alteration in LINGO1 mRNA was observed between groups in either the cerebellar cortex or the white matter. We observed alterations in LINGO expression in diseased brain that seemed to progress along with the disease, being initiated in the cerebellar cortex before reaching the white matter. Because LINGO up-regulation has been identified as a potential pathological response to ongoing neurodegenerative processes, the present data suggest that LINGO1 is a potential drug target for ET.
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Cerebelo/metabolismo , Temblor Esencial/patología , Regulación de la Expresión Génica/fisiología , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Anciano , Anciano de 80 o más Años , Cerebelo/patología , Femenino , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , ARN Mensajero/metabolismo , Sustancia Blanca/metabolismo , Sustancia Blanca/patologíaRESUMEN
BACKGROUND: Families of Dutch-German-Russian Mennonite descent with multi-incident parkinsonism have been identified as harboring a pathogenic DNAJC13 p.N855S mutation and are awaiting clinical and pathophysiological characterization. METHODS: Family members were examined clinically longitudinally, and 5 underwent dopaminergic PET imaging. Four family members came to autopsy. RESULTS: Of the 16 symptomatic DNAJC13 mutation carriers, 12 had clinically definite, 3 probable, and 1 possible Parkinson's disease (PD). Symptoms included bradykinesia, tremor, rigidity, and postural instability, with a mean onset of 63 years (range, 40-85) and slow progression. Eight of ten subjects who required treatment had a good levodopa response; motor complications and nonmotor symptoms were observed. Dopaminergic PET imaging revealed rostrocaudal striatal deficits typical for idiopathic PD in established disease and subtle abnormalities in incipient disease. Pathological examinations revealed Lewy body pathology. CONCLUSION: PD associated with a DNAJC13 p.N855S mutation presents as late-onset, often slowly progressive, usually dopamine-responsive typical PD.
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Encéfalo/diagnóstico por imagen , Chaperonas Moleculares/genética , Mutación/genética , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/genética , Tomografía de Emisión de Positrones , Anciano , Anciano de 80 o más Años , Encéfalo/efectos de los fármacos , Isótopos de Carbono/farmacocinética , Dopaminérgicos/farmacocinética , Salud de la Familia , Fluorodesoxiglucosa F18 , Humanos , Levodopa/farmacocinética , Persona de Mediana Edad , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacocinéticaRESUMEN
OBJECTIVES: The aim of the study is to report a case with heat intolerance, complex motor fluctuations, and parkinsonism. MATERIALS AND METHODS: A male with onset of heat intolerance at the age of 46 years developed left upper limb tremor at the age of 58 years. He was diagnosed with Parkinson disease at the age of 62 years and presented to Movement Disorders Clinic Saskatchewan at the age of 65 years. He reported motor response fluctuations, including WO and dyskinesias. There was no history of dizziness on standing, bladder, or sexual dysfunction. We recorded an asymptomatic drop of orthostatic blood pressure. He reported loss of smell sensation for 5 years and REM behavior disorder characterized by talking in his sleep. He was assessed at the age of 65 years over the course of a day with 4 video recordings of his evolving findings and symptoms with his informed consent. RESULTS: Initial assessment after levodopa was withheld more than 14 hours revealed him to be 'off' with severe dystonic neck flexion and with bradykinesia and rigidity in the limbs. He was anhidrotic, felt hot, and needed a wet towel over his neck. Over the course of 4 hours, he turns "on" with improvement in heat intolerance, neck hypertonicity, and parkinsonian findings and develops evolving dyskinetic movements before turning "off" again. His overall clinical picture was most consistent with multiple system atrophy. CONCLUSIONS: Heat intolerance can precede onset of motor symptoms of parkinsonism by several years and supports a diagnosis of multiple system atrophy. To our knowledge, this is the first documented case of improvement in heat intolerance with levodopa.
Asunto(s)
Levodopa , Enfermedad de Parkinson , Anciano , Humanos , Masculino , Calor , Levodopa/uso terapéutico , Atrofia de Múltiples Sistemas , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with a notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as a subset are both regulators and substrates of LRRK2 protein kinase. To explore the role of RAB GTPases in PD, we undertook a comprehensive examination of their genetic variability in familial PD. Methods: Affected probands from 130 multi-incident PD families underwent whole-exome sequencing and genotyping, Potential pathogenic variants in 61 RAB GTPases were genotyped in relatives to assess disease segregation. These variants were also genotyped in a larger case-control series, totaling 3,078 individuals (2,734 with PD). The single most significant finding was subsequently validated within genetic data (6,043 with PD). Clinical and pathologic findings were summarized for gene-identified patients, and haplotypes were constructed. In parallel, wild-type and mutant RAB GTPase structural variation, protein interactions, and resultant enzyme activities were assessed. Findings: We found RAB32 c.213C>G (Ser71Arg) to co-segregate with autosomal dominant parkinsonism in three multi-incident families. RAB32 Ser71Arg was also significantly associated with PD in case-control samples: genotyping and database searches identified thirteen more patients with the same variant that was absent in unaffected controls. Notably, RAB32 Ser71Arg heterozygotes share a common haplotype. At autopsy, one patient had sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In transfected cells the RAB32 Arg71 was twice as potent as Ser71 wild type to activate LRRK2 kinase. Interpretation: Our study provides unequivocal evidence to implicate RAB32 Ser71Arg in PD. Functional analysis demonstrates LRRK2 kinase activation. We provide a mechanistic explanation to expand and unify the etiopathogenesis of monogenic PD. Funding: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J. Fox Foundation for Parkinson's Research, and the UK Medical Research Council.