RESUMEN
BACKGROUND: Colony-stimulating factor 1 receptor (CSF1R)-related disorder (CRD) is a rare autosomal dominant disease. The clinical and genetic characteristics of Chinese patients have not been elucidated. OBJECTIVE: The objective of the study is to clarify the core features and influence factors of CRD patients in China. METHODS: Clinical and genetic-related data of CRD patients in China were collected. Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Sundal MRI Severity Score were evaluated. Whole exome sequencing was used to analyze the CSF1R mutation status. Patients were compared between different sexes, mutation types, or mutation locations. RESULTS: A total of 103 patients were included, with a male-to-female ratio of 1:1.51. The average age of onset was (40.75 ± 8.58). Cognitive impairment (85.1%, 86/101) and parkinsonism (76.2%, 77/101) were the main clinical symptoms. The most common imaging feature was bilateral asymmetric white matter changes (100.0%). A total of 66 CSF1R gene mutants (22 novel mutations) were found, and 15 of 92 probands carried c.2381 T > C/p.I794T (16.30%). The MMSE and MoCA scores (17.0 [9.0], 11.90 ± 7.16) of female patients were significantly lower than those of male patients (23.0 [10.0], 16.36 ± 7.89), and the white matter severity score (20.19 ± 8.47) of female patients was significantly higher than that of male patients (16.00 ± 7.62). There is no statistical difference in age of onset between male and female patients. CONCLUSIONS: The core manifestations of Chinese CRD patients are progressive cognitive decline, parkinsonism, and bilateral asymmetric white matter changes. Compared to men, women have more severe cognitive impairment and imaging changes. c.2381 T > C/p.I794T is a hotspot mutation in Chinese patients. © 2024 International Parkinson and Movement Disorder Society.
Asunto(s)
Mutación , Fenotipo , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , China/epidemiología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Mutación/genética , Genotipo , Disfunción Cognitiva/genética , Imagen por Resonancia Magnética , Trastornos Parkinsonianos/genética , Anciano , Edad de Inicio , Adulto Joven , Receptor de Factor Estimulante de Colonias de MacrófagosRESUMEN
The accumulation of microglia around senile plaques is one of the pathological features of Alzheimer's disease (AD). Chemerin is an adipokine with immune-modulating properties. Our previous study showed that chemokine-like receptor 1 (CMKLR1), the receptor for chemerin, is also a functional receptor of Aß. However, it remains unclear whether and how the chemerin/CMKLR1 axis affects the migration of microglia. The impact of CMKLR1 on microglial activation and recruitment toward Aß deposits was examined in APP/PS1 mice mated with CMKLR1 knockout (CMKLR1-/-) mice. CMKLR1 deficiency reduced the number of microglia around Aß deposits in aged APP/PS1-CMKLR1-/- mice compared with APP/PS1 mice. Chemerin expression was significantly decreased in the hippocampus and cortex of aged APP/PS1 mice compared with WT mice. In vitro assays demonstrated that activation of the chemerin/CMKLR1 axis promoted the migration of primary cultures of microglia and murine microglial N9 cells. Mechanistic studies found that chemerin/CMKLR1 induced polarization and protrusion formation of microglia by promoting the remodeling of actin filaments and microtubules, and Golgi apparatus reorientation. The inhibition of p38 MAPK attenuated the promotion of the chemerin/CMKLR1 axis on microglial migration and polarization. In addition, chemerin inhibited Aß-induced microglial clustering. The inhibition of p38 MAPK alleviated the suppressive effect of chemerin on Aß-induced microglial aggregation. Our data indicate that the chemerin/CMKLR1 axis is involved in the migration and recruitment of microglia to senile plaques via the p38 MAPK pathway. Modulation of the chemerin/CMKLR1 axis is a potential new strategy for AD therapy.
Asunto(s)
Enfermedad de Alzheimer , Quimiocinas , Péptidos y Proteínas de Señalización Intercelular , Microglía , Receptores de Quimiocina , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Quimiocinas/metabolismo , Modelos Animales de Enfermedad , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ratones , Ratones Transgénicos , Microglía/metabolismo , Placa Amiloide/metabolismo , Receptores de Quimiocina/genética , Receptores de Quimiocina/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
In the original publication [...].