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1.
Int J Mol Sci ; 23(16)2022 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-36012622

RESUMEN

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease classified as both a neurodegenerative and neuromuscular disorder. With a complex aetiology and no current cure for ALS, broadening the understanding of disease pathology and therapeutic avenues is required to progress with patient care. Alpha-synuclein (αSyn) is a hallmark for disease in neurodegenerative disorders, such as Parkinson's disease, Lewy body dementia, and multiple system atrophy. A growing body of evidence now suggests that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43. This review endeavours to capture the scope of literature regarding the aetiology and development of ALS and its commonalities with "synucleinopathy disorders". We will discuss the involvement of αSyn in ALS and motor neuron disease pathology, and the current theories and strategies for therapeutics in ALS treatment, as well as those targeting αSyn for synucleinopathies, with a core focus on small molecule RNA technologies.


Asunto(s)
Esclerosis Amiotrófica Lateral , Enfermedad por Cuerpos de Lewy , Atrofia de Múltiples Sistemas , Sinucleinopatías , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/terapia , Humanos , Cuerpos de Lewy/metabolismo , Enfermedad por Cuerpos de Lewy/patología , Atrofia de Múltiples Sistemas/patología , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
2.
J Neurosci Res ; 92(4): 506-16, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24375786

RESUMEN

Mutations in the leucine-rich repeat kinase 2 (lrrk2) gene are the leading genetic cause of Parkinson's disease (PD). In characterizing the novel ROC domain mutant A1442P, we compared its steady-state protein levels, propensity to aggregate, and toxicity with the pathogenic R1441C mutant and wild-type (WT) LRRK2. Mutant (R1441C and A1442P) and WT LRRK2 fused to green fluorescent protein (GFP) and FLAG were transiently expressed in HEK293 cells using plasmid constructs. Western analysis and fluorescence microscopy consistently demonstrated lower mutant LRRK2 protein levels compared with WT. A time-course expression study using flow cytometry showed that WT LRRK2 expression increased initially but then plateaued by 72 hr. Conversely, R1441C and A1442P mutant expression attained 85% and 74% of WT levels at 24 hr but fell to 68% and 55% of WT levels by 72 hr, respectively. We found that proteasome inhibition markedly increased mutant LRRK2 to levels approaching those of WT. Taken together, our findings reveal increased intracellular degradation for both mutants. Furthermore, the impact of mutant and WT LRRK2 expression on HEK293 cell viability was assessed under normative and oxidative (hydrogen peroxide) conditions and found not to differ. Expression of WT and mutant LRRK2 protein gave rise to intracellular aggregates of similar appearance and cellular localization. In summary, we provide evidence that the novel A1442P mutant and the previously investigated R1441C pathogenic mutant exhibit increased intracellular degradation, a property reportedly demonstrated for the pathogenic LRRK2 kinase domain mutant I2020T.


Asunto(s)
Regulación de la Expresión Génica/genética , Mutación/genética , Proteínas Serina-Treonina Quinasas/genética , Aminoácidos/genética , Análisis de Varianza , Supervivencia Celular , Inhibidores de Cisteína Proteinasa/farmacología , Citometría de Flujo , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Células HEK293 , Humanos , Peróxido de Hidrógeno/farmacología , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Leupeptinas/farmacología , Factores de Tiempo , Transfección
3.
J Neuroeng Rehabil ; 11: 31, 2014 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-24597619

RESUMEN

BACKGROUND: A peripheral nerve stimulus can enhance or suppress the evoked response to transcranial magnetic stimulation (TMS) depending on the latency of the preceding peripheral nerve stimulation (PNS) pulse. Similarly, somatosensory afference from the passively moving limb can transiently alter corticomotor excitability, in a phase-dependent manner. The repeated association of PNS with TMS is known to modulate corticomotor excitability; however, it is unknown whether repeated passive-movement associative stimulation (MAS) has similar effects. METHODS: In a proof-of-principal study, using a cross-over design, seven healthy subjects received in separate sessions: (1) TMS (120% of the resting motor threshold-RMT, optimal site for Flexor Carpi Radialis) with muscle at rest; (2) TMS paired with cyclic passive movement during extension cyclic passive movement (400 pairs, 1 Hz), with the intervention order randomly assigned. Normality was tested using the Kolmogorov-Smirnov test, then compared to pre-intervention baseline using repeated measures ANOVA with a Dunnet multiple comparisons test. RESULTS: MAS led to a progressive and significant decrease in the motor evoked potential (MEP) amplitude over the intervention (R(2) = 0.6665, P < 0.0001), which was not evident with TMS alone (R(2) = 0.0068, P = 0.641). Post-intervention excitability reduction, only present with MAS intervention, remained for 20 min (0-10 min = 68.2 ± 4.9%, P < 0.05; 10-20 min = 73.3 ± 9.7%, P < 0.05). CONCLUSION: The association of somatosensory afference from the moving limb with TMS over primary motor cortex in healthy subjects can be used to modulate corticomotor excitability, and may have therapeutic implications.


Asunto(s)
Potenciales Evocados Motores/fisiología , Corteza Motora/fisiología , Movimiento/fisiología , Estimulación Magnética Transcraneal/métodos , Adulto , Estudios Cruzados , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
4.
Dysphagia ; 27(1): 64-9, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21442390

RESUMEN

This study compared self-reported incidence and prevalence of dysphagia in inflammatory myopathy diseases with instrumental data from videofluoroscopy in a cohort of 18 patients with inflammatory myopathies (inclusion body myositis, polymyositis, and dermatomyositis). We found a high self-report of incidence of dysphagia and demonstrated that symptoms described by the patients follow a characteristic pattern. We conclude that there is a high incidence of dysphagia in all three of the inflammatory myopathies. Questions about swallowing should routinely be included in inflammatory myopathy patient examinations in order to appropriately refer patients for further investigation of their swallowing function and avoid the complications associated with dysphagia.


Asunto(s)
Trastornos de Deglución/etiología , Miositis/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Sulfato de Bario , Estudios de Cohortes , Medios de Contraste , Trastornos de Deglución/diagnóstico por imagen , Trastornos de Deglución/epidemiología , Femenino , Fluoroscopía , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Prevalencia , Autoinforme , Grabación en Video
5.
J Assoc Nurses AIDS Care ; 30(1): 42-50, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30586348

RESUMEN

Neurocognitive impairment (NCI) is common in people aging with HIV and can adversely affect health-related quality of life. However, early NCI may be largely asymptomatic and neurocognitive function is rarely assessed in the context of routine clinical care. In this study, we considered the utility of two assessment tools as screens for NCI in patients attending a community-based clinic (N = 58; mean age = 57 years): the Montreal Cognitive Assessment (MoCA) and a 3-item cognitive concerns questionnaire derived from the HIV Dementia Scale. Health-related quality of life and depression/anxiety were also measured. Indication of NCI using the MoCA was more prevalent compared to the 3-item questionnaire and was associated with the patients' initial antiretroviral therapy commencing between the years of 1997 and 2001, independently of age. Findings of the MoCA were not confounded by existing mood disorders, unlike the 3-item questionnaire. Therefore, we suggest implementing the MoCA as an initial screen for NCI.


Asunto(s)
Complejo SIDA Demencia/diagnóstico , Ansiedad/psicología , Trastornos del Conocimiento/diagnóstico , Infecciones por VIH/complicaciones , Pruebas de Estado Mental y Demencia/normas , Calidad de Vida , Complejo SIDA Demencia/psicología , Adulto , Terapia Antirretroviral Altamente Activa/métodos , Ansiedad/epidemiología , Trastornos del Conocimiento/psicología , Depresión/epidemiología , Depresión/psicología , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/psicología , Humanos , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Pruebas Neuropsicológicas , Prevalencia , Escalas de Valoración Psiquiátrica , Encuestas y Cuestionarios
6.
J Neuromuscul Dis ; 3(1): 67-75, 2016 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-27854208

RESUMEN

BACKGROUND: There is a paucity of data on mortality and causes of death (CoDs) in patients with sporadic inclusion body myositis (sIBM), a rare, progressive, degenerative, inflammatory myopathy that typically affects those aged over 50 years. OBJECTIVE: Based on patient records and expertise of clinical specialists, this study used questionnaires to evaluate physicians' views on clinical characteristics of sIBM that may impact on premature mortality and CoDs in these patients. METHODS: Thirteen physicians from seven countries completed two questionnaires online between December 20, 2012 and January 15, 2013. Responses to the first questionnaire were collated and presented in the second questionnaire to seek elaboration and identify consensus. RESULTS: All 13 physicians completed both questionnaires, providing responses based on 585 living and 149 deceased patients under their care. Patients were reported to have experienced dysphagia (60.2%) and injurious falls (44.3%) during their disease. Over half of physicians reported that a subset of their patients with sIBM had a shortened lifespan (8/13), and agreed that bulbar dysfunction/dysphagia/oropharyngeal involvement (12/13), early-onset disease (8/13), severe symptoms (8/13), and falls (7/13) impacted lifespan. Factors related to sIBM were reported as CoDs in 40% of deceased patients. Oropharyngeal muscle dysfunction was ranked as the leading feature of sIBM that could contribute to death. The risk of premature mortality was higher than the age-matched comparison population. CONCLUSIONS: In the absence of data from traditional sources, this study suggests that features of sIBM may contribute to premature mortality and may be used to inform future studies.


Asunto(s)
Causas de Muerte , Mortalidad Prematura , Miositis por Cuerpos de Inclusión/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Europa (Continente)/epidemiología , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Médicos/estadística & datos numéricos , Estados Unidos/epidemiología
7.
Front Aging Neurosci ; 7: 16, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25741279

RESUMEN

Cognitive decline and dementia due to Alzheimer's disease (AD) have been associated with genetic, lifestyle, and environmental factors. A number of potentially modifiable risk factors should be taken into account when preventive or ameliorative interventions targeting dementia and its preclinical stages are investigated. Bone mineral density (BMD) and body composition are two such potentially modifiable risk factors, and their association with cognitive decline was investigated in this study. 164 participants, aged 34-87 years old (62.78 ± 9.27), were recruited for this longitudinal study and underwent cognitive and clinical examinations at baseline and after 3 years. Blood samples were collected for apolipoprotein E (APOE) genotyping and dual energy x-ray absorptiometry (DXA) was conducted at the same day as cognitive assessment. Using hierarchical regression analysis, we found that BMD and lean body mass, as measured using DXA were significant predictors of episodic memory. Age, gender, APOE status, and premorbid IQ were controlled for. Specifically, the List A learning from California Verbal Learning Test was significantly associated with BMD and lean mass both at baseline and at follow up assessment. Our findings indicate that there is a significant association between BMD and lean body mass and episodic verbal learning. While the involvement of modifiable lifestyle factors in human cognitive function has been examined in different studies, there is a need for further research to understand the potential underlying mechanisms.

8.
J Alzheimers Dis ; 39(3): 545-56, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24217276

RESUMEN

The CD147 protein is a ubiquitous multifunctional membrane receptor. Expression of CD147, which is regulated by sterol carrier protein, reportedly modulates amyloid-ß (Aß), the neurotoxic peptide implicated in neuronal degeneration in Alzheimer's disease (AD). Given that high fat/cholesterol is linked to amyloid deposition in AD, we investigated if cholesterol and/or Aß can alter CD147 expression in rat cortical neuronal cultures. Water-soluble cholesterol and Aß42 dose-dependently increased CD147 protein expression, but reduced FL-AßPP protein expression. Cholesterol and Aß42 treatment also increased lactate dehydrogenase release but to varying degrees. Upregulation of CD147 expression was probably mediated by oxidative stress, as H2O2 (3 µM) also induced CD147 protein expression in neuronal cultures. In light of these findings, we investigated if CD147 induction was cytoprotective, a compensatory response to injury, or alternatively, a cell death signal. To this end, we used recombinant adenovirus to overexpress human CD147 (in SH-SY5Y cells and primary cortical neurons), and pre-treated cultures with or without recombinant cyclophilin A (rCYPA) protein, prior to Aß42 exposure. We showed that increased CD147 expression protected against Aß42, only when rCYPA protein was added to neuronal cultures. Together, our findings reveal potentially important relationships between cholesterol loading, CD147 expression, Aß toxicity, and the putative involvement of CYPA protein in neuroprotection in AD.


Asunto(s)
Péptidos beta-Amiloides/farmacología , Basigina/metabolismo , Colesterol/farmacología , Ciclofilina A/metabolismo , Peróxido de Hidrógeno/farmacología , Neuronas/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Células Cultivadas , Corteza Cerebral/citología , Ciclofilina A/genética , Relación Dosis-Respuesta a Droga , Embrión de Mamíferos , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , L-Lactato Deshidrogenasa/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción Genética
9.
Neurobiol Aging ; 33(6): 1054-6, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20961668

RESUMEN

A number of genetic risk factors have been identified for Alzheimer's disease (AD) including genes involved in the inflammatory response (interleukin 1A, [IL-1α (-889)], interleukin 1B (IL-1ß [+3953]), and tumor necrosis factor (TNF [-308 and -850]). We investigated the prevalence and functional consequences (baseline cognitive performance, plasma cytokine levels) of possession of these putative genetic risk factors within a group of subjective memory complainers (SMC, n = 226) and age and sex matched noncomplainers (NMC, n = 167). We observed no effect of any of the genetic factors investigated on cognitive performance. Further, there was no difference in the frequency of the disease-associated alleles, or cytokine levels between subjective memory complainers and noncomplainer participants. There was no relationship between TNF polymorphisms and TNF levels. There was a significant increase in plasma IL-1ß levels in those homozygous for the disease-associated allele (i.e., IL-1ß +3953 TT). Follow-up longitudinal assessments on this cohort will provide insight as to how these polymorphisms may affect the risk of cognitive decline over time.


Asunto(s)
Mediadores de Inflamación/fisiología , Memoria/fisiología , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Interleucina-1alfa/genética , Interleucina-1beta , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/genética
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