-
The Journal of Biological Chemistry Apr 2024Experimental studies in flies, mice, and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer's disease (AD). The mechanisms...
Experimental studies in flies, mice, and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer's disease (AD). The mechanisms underlying these impairments in axonal transport, however, remain poorly understood. Here we report that the Swedish familial AD mutation causes a standstill of the amyloid precursor protein (APP) in the axons at the expense of its reduced anterograde transport. The standstill reflects the perturbed directionality of the axonal transport of APP, which spends significantly more time traveling in the retrograde direction. This ineffective movement is accompanied by an enhanced association of dynactin-1 with APP, which suggests that reduced anterograde transport of APP is the result of enhanced activation of the retrograde molecular motor dynein by dynactin-1. The impact of the Swedish mutation on axonal transport is not limited to the APP vesicles since it also reverses the directionality of a subset of early endosomes, which become enlarged and aberrantly accumulate in distal locations. In addition, it also reduces the trafficking of lysosomes due to their less effective retrograde movement. Altogether, our experiments suggest a pivotal involvement of retrograde molecular motors and transport in the mechanisms underlying impaired axonal transport in AD and reveal significantly more widespread derangement of axonal transport pathways in the pathogenesis of AD.
Topics: Animals; Humans; Mice; Alzheimer Disease; Amyloid beta-Protein Precursor; Axonal Transport; Axons; Dynactin Complex; Dyneins; Endosomes; Lysosomes; Mutation; Genetic Variation
PubMed: 38447793
DOI: 10.1016/j.jbc.2024.107137 -
The American Journal of Case Reports Mar 2024BACKGROUND Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disease that can present at different ages with different phenotypes. Missed and delayed...
BACKGROUND Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disease that can present at different ages with different phenotypes. Missed and delayed diagnoses are fairly common. Many variants in the DNAH5 gene have been described that confirm the diagnosis of PCD. Advances in medicine, especially in molecular genetics, have led to increasingly early discoveries of such cases, especially in those with nonclassical presentations. CASE REPORT This report describes a patient with bronchiectasis, lung cysts, finger clubbing, and failure to thrive who was misdiagnosed for several years as having asthma. Many differentials were suspected and worked up, including a suspicion of PCD. Genetic tests with whole-exome sequencing (WES) and whole-genome sequencing (WGS) detected a heterozygous, likely pathogenic, variant in the DNAH5 gene associated with PCD. CONCLUSIONS Despite a thorough workup done for this case, including a genetic workup, a PCD diagnosis was not established. We plan to reanalyze the WGS in the future, and with advent of technology and better coverage of genes, a genetic answer for this challenging case may resolve this diagnostic quandary in the future.
Topics: Humans; Axonemal Dyneins; Genetic Testing; Kartagener Syndrome; Lung; Mutation
PubMed: 38521969
DOI: 10.12659/AJCR.942444 -
The Journal of Maternal-fetal &... Dec 2023Short-rib thoracic dysplasia 3 with or without polydactyly (OMIM # 613091) represents a clinical spectrum encompassing a heterogeneous group of skeletal dysplasias...
Early prenatal diagnosis of a recurrent case of short-rib thoracic dysplasia 3 due to compound heterozygosity for variations in the DYNC2H1 gene: an "ultrasound first" approach.
Short-rib thoracic dysplasia 3 with or without polydactyly (OMIM # 613091) represents a clinical spectrum encompassing a heterogeneous group of skeletal dysplasias associated with homozygous or compound heterozygous mutations of DYNC2H1. We describe the case of a couple with two consecutive therapeutic abortions due to a diagnosis of short-rib thoracic dysplasia mutations. In the first pregnancy, the diagnosis has been made at 21 weeks. In the second one, an accurate and early ultrasound examination allowed a diagnosis at 12 weeks. DYNC2H1 mutations were confirmed in both cases. In this report, we underline the importance of an ultrasound evaluation at the end of the first trimester of pregnancy in the detection of early signs of skeletal dysplasias. An early prenatal diagnosis of a short-rib skeletal dysplasia, such as for other severe skeletal dysplasias, is critical to offer a couple the chance of a weighted, informed, and less traumatic decision about the continuation of the pregnancy.
Topics: Pregnancy; Female; Humans; Short Rib-Polydactyly Syndrome; Prenatal Diagnosis; Ultrasonography; Osteochondrodysplasias; Ribs; Ultrasonography, Prenatal; Cytoplasmic Dyneins
PubMed: 37100787
DOI: 10.1080/14767058.2023.2205985