Modeling Hereditary Diffuse Leukoencephalopathy with Axonal Spheroids using microglia-sufficient brain organoids
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ABSTRACT:
PROVIDER: PRJNA1133661 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29754100_1.fastq.gz | Fastqsanger.gz | |||
| SRR29754100_2.fastq.gz | Fastqsanger.gz | |||
| SRR29754101_1.fastq.gz | Fastqsanger.gz | |||
| SRR29754101_2.fastq.gz | Fastqsanger.gz | |||
| SRR29754102_1.fastq.gz | Fastqsanger.gz |
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Project description:Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare, fatal, adult-onset neurodegenerative disease that is most often caused by mutations affecting the Colony Stimulating factor-1 Receptor (CSF-1R). To understand how CSF-1R-mutation affects human microglia – the specialized brain-resident macrophages of the central nervous system – and the downstream consequences for neuronal cells, we used a macrophage and forebrain organoid co-culture system based on induced pluripotent stem cells generated from two patients with HDLS, with CSF-1R gene-corrected isogenic organoids as controls. Macrophages derived from iPSC (iMacs) of patients exhibited a metabolic shift towards the glycolytic pathway and reduced CSF-1 sensitivity, which was associated with higher levels of IL-1β production and an activated inflammatory phenotype. Single-cell RNA sequencing revealed that iMacs adopt a reactive state that leads to impaired regulation of neuronal cell populations in organoid cultures, thereby identifying microglial dysregulation and specifically IL-1β production as key contributors to the degenerative neuro-environment in HDLS.
2024-12-31 | GSE271810 | GEO
Project description:Microglia, the brain's resident macrophages, depend on interleukin 34 (IL-34) and colony-stimulating factor 1 (CSF1) for their development and maintenance, engaging the CSF1 receptor (CSF1R). Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a neurodegenerative disorder affecting the brain's white matter, is caused by heterozygous pathogenic mutations in the CSF1R gene. Neuropathological studies of postmortem ALSP brains have shown widespread depletion of microglia, demyelination of cerebral white matter, axonal swellings, and pigmented glial cells. In this study, we investigated how individual brain cell populations respond to microglia depletion and contribute to ALSP progression. To do this, we analyzed post-mortem specimens from patients wirth ALSP using single-nucleus RNA-seq (snRNA-seq).
2025-08-13 | GSE295854 | GEO
Project description:Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant disease clinically characterized by cognitive decline, personality changes, motor impairment, parkinsonism and seizures. Recently, mutations in the colony-stimulating factor-1 receptor (CSF1R) gene have been shown to be associated with HDLS. We report clinical, neuropathological and molecular genetic findings of patients from a new family with a mutation in the CSF1R gene. Disease onset was earlier and disease progression was more rapid compared with previously reported patients. Psychiatric symptoms including personality changes, alcohol abuse and severe depression were the first symptoms in male patients. In the index, female patient, the initial symptom was cognitive decline. Magnetic resonance imaging (MRI) showed bilateral, confluent white matter lesions in the cerebrum. Stereotactic biopsy revealed loss of myelin and microglial activation as well as macrophage infiltration of the parenchyma. Numerous axonal swellings and spheroids were present. Ultrastructural analysis revealed pigment-containing macrophages. Axonal swellings were detected by electron microscopy not only in the central nervous system (CNS) but also in skin nerves. We identified a heterozygous mutation (c.2330G>A, p.R777Q) in the CSF1R gene. Through this report, we aim to enlarge the nosological spectrum of HDLS, providing new clinical descriptions as well as novel neuropathological findings from the peripheral nervous system.
| S-EPMC8029294 | biostudies-literature
Project description:We report a family with a novel CSF1R mutation causing hereditary diffuse leucoencephalopathy with axonal spheroids. Family members presented with neuropsychiatric and behavioural symptoms, with subsequent development of motor symptoms and gait disturbance. MRI brain showed extensive white matter change with a frontal predominance and associated atrophy in two members of the family. Genetic testing revealed a novel mutation c.2342C>T (p.A781V) in the CSF1R gene in two brothers of the family. This report highlights the difficulties in diagnosing HDLS and discusses the indications for testing for mutations in the CSF1R gene.
| S-EPMC3750216 | biostudies-literature
Project description:BACKGROUND:Hereditary diffuse leukodystrophy with spheroids is a rare type of leukoencephalopathy. Mutations in the colony stimulating factor 1 receptor have recently been identified to be the cause of this microgliopathy. Clinical and radiological presentation can often misguide physicians during the diagnosis of patients with this underdiagnosed disease. CASE PRESENTATION:We present a 29 year-old woman with a rapid course of hereditary diffuse leukodystrophy with spheroids. She mainly showed cognitive impairment and severe motor dysfunctions. Her MRI showed spotted and confluent hyperintensities of the white matter on T2-weighted images involving the corticospinal tract as well as the corpus callosum. Further, those lesions showed striking restricted diffusion. As this restricted diffusion in all areas showing signs of leukoencephalopathy was so impressive we searched Medline for these terms and got hereditary diffuse leukodystrophy with spheroids as one of the first results. After a comprehensive diagnostic workup and exclusion of other leukoencephalopathies, stereotactic biopsy and genetic testing confirmed the diagnosis. CONCLUSION:This case points out at two important features of hereditary diffuse leukodystrophy with spheroids being spotted and/or confluent leukoencephalopathy with areas of restricted diffusion. This might help to identify more patients with this underdiagnosed disease. Moreover, the rapid clinical course in our patient raises the question whether the relatively pronounced areas of restricted diffusion are indicative of a more acute progression of the disease.
| S-EPMC4491230 | biostudies-literature
Project description:Early motor symptoms of neurodegenerative diseases often appear in combination with psychiatric symptoms, such as depression or personality changes, and are in danger of being misdiagnosed as psychogenic in young patients. We present the case of a 32-year-old woman who presented with rapid-onset depression, followed by a hypokinetic movement disorder and cognitive decline during pregnancy. Genetic testing revealed a mutation in the colony-stimulating factor 1 receptor gene, which led to the diagnosis of hereditary diffuse leukoencephalopathy with spheroids. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is probably an under-recognized disease. HDLS should be considered in patients with rapidly progressing parkinsonian symptoms and dementia accompanied by white matter lesions.
| S-EPMC5288666 | biostudies-literature
Project description:Mutations in the colony stimulating factor 1 receptor (CSF1R) have recently been discovered as causal for hereditary diffuse leukoencephalopathy with axonal spheroids. We identified a novel, heterozygous missense mutation in CSF1R [c.1990G > A p.(E664K)] by exome sequencing in five members of a family with hereditary diffuse leukoencephalopathy with axonal spheroids. Three affected siblings had characteristic white matter abnormalities and presented with progressive neurological decline. In the fourth affected sibling, early progression halted after allogeneic haematopoietic stem cell transplantation from a related donor. Blood spot DNA from this subject displayed chimerism in CSF1R acquired after haematopoietic stem cell transplantation. Interestingly, both parents were unaffected but the mother's blood and saliva were mosaic for the CSF1R mutation. Our findings suggest that expression of wild-type CSF1R in some cells, whether achieved by mosaicism or chimerism, may confer benefit in hereditary diffuse leukoencephalopathy with axonal spheroids and suggest that haematopoietic stem cell transplantation might have a therapeutic role for this disorder.
| S-EPMC4892751 | biostudies-literature
Project description:Denunded HUVEC/HUASMC spheroids vs. HUASMC spheroids
| PRJNA657248 | ENA
Project description:Atypical Parkinsonism associated with white matter pathology has been described in cerebrovascular diseases, mitochondrial cytopathies, osmotic demyelinating disorders, leukoencephalopathies leukodystrophies, and others. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder with symptomatic onset in midlife and death within a few years after symptom onset. Neuroimaging reveals cerebral white matter lesions that are pathologically characterized by non-inflammatory myelin loss, reactive astrocytosis, and axonal spheroids. Most cases are caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. We studied neuropathologically verified HDLS patients with CSF1R mutations to assess parkinsonian features. Ten families were evaluated with 16 affected individuals. During the course of the illness, all patients had at least some degree of bradykinesia. Fifteen patients had postural instability, and seven had rigidity. Two patients initially presented with parkinsonian gait and asymmetrical bradykinesia. These two patients and two others exhibited bradykinesia, rigidity, postural instability, and tremor (two with resting) early in the course of the illness. Levodopa/carbidopa therapy in these four patients provided no benefit, and the remaining 12 patients were not treated. The mean age of onset for all patients was about 45 years (range, 18-71) and the mean disease duration was approximately six years (range, 3-11). We also reviewed HDLS patients published prior to the CSF1R discovery for the presence of parkinsonian features. Out of 50 patients, 37 had gait impairments, 8 rigidity, 7 bradykinesia, and 5 resting tremor. Our report emphasizes the presence of atypical Parkinsonism in HDLS due to CSF1R mutations.
| S-EPMC3977389 | biostudies-literature