172 research outputs found
Spinocerebellar ataxia type 19/22 mutations alter heterocomplex Kv4.3 channel function and gating in a dominant manner
The dominantly inherited cerebellar ataxias are a heterogeneous group of neurodegenerative disorders caused by Purkinje cell loss in the cerebellum. Recently, we identified loss-of-function mutations in the KCND3 gene as the cause of spinocerebellar ataxia type 19/22 (SCA19/22), revealing a previously unknown role for the voltage-gated potassium channel, Kv4.3, in Purkinje cell survival. However, how mutant Kv4.3 affects wild-type Kv4.3 channel functioning remains unknown. We provide evidence that SCA19/22-mutant Kv4.3 exerts a dominant negative effect on the trafficking and surface expression of wild-type Kv4.3 in the absence of its regulatory subunit, KChIP2. Notably, this dominant negative effect can be rescued by the presence of KChIP2. We also found that all SCA19/22-mutant subunits either suppress wild-type Kv4.3 current amplitude or alter channel gating in a dominant manner. Our findings suggest that altered Kv4.3 channel localization and/or functioning resulting from SCA19/22 mutations may lead to Purkinje cell loss, neurodegeneration and ataxia
ΠΠ΅Π³ΠΎΡΠ½Π°Ρ Π³ΠΈΠΏΠ΅ΡΡΠ΅Π½Π·ΠΈΡ ΠΏΡΠΈ Π΄ΠΈΠ°ΡΡΠΎΠ»ΠΈΡΠ΅ΡΠΊΠΎΠΉ Π΄ΠΈΡΡΡΠ½ΠΊΡΠΈΠΈ Π»Π΅Π²ΠΎΠ³ΠΎ ΠΆΠ΅Π»ΡΠ΄ΠΎΡΠΊΠ° Ρ Π±ΠΎΠ»ΡΠ½ΡΡ Ρ ΠΈΡΠ΅ΠΌΠΈΡΠ΅ΡΠΊΠΎΠΉ ΠΊΠ°ΡΠ΄ΠΈΠΎΠΌΠΈΠΎΠΏΠ°ΡΠΈΠ΅ΠΉ
ΠΠ° ΠΎΡΠ½ΠΎΠ²Π°Π½ΠΈΠΈ Π΄Π°Π½Π½ΡΡ
ΡΡ
ΠΎΠΊΠ°ΡΠ΄ΠΈΠΎΠ³ΡΠ°ΡΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ Π²ΡΡΠ²Π»Π΅Π½Π° Π²Π·Π°ΠΈΠΌΠΎΡΠ²ΡΠ·Ρ ΠΌΠ΅ΠΆΠ΄Ρ ΡΡΠ΅ΠΏΠ΅Π½ΡΡ Π»Π΅Π³ΠΎΡΠ½ΠΎΠΉ Π³ΠΈΠΏΠ΅ΡΡΠ΅Π½Π·ΠΈΠΈ ΠΈ ΡΡΠΆΠ΅ΡΡΡΡ Π΄ΠΈΠ°ΡΡΠΎΠ»ΠΈΡΠ΅ΡΠΊΠΎΠΉ Π΄ΠΈΡΡΡΠ½ΠΊΡΠΈΠΈ Π»Π΅Π²ΠΎΠ³ΠΎ ΠΆΠ΅Π»ΡΠ΄ΠΎΡΠΊΠ° Ρ Π±ΠΎΠ»ΡΠ½ΡΡ
Ρ ΠΈΡΠ΅ΠΌΠΈΡΠ΅ΡΠΊΠΎΠΉ ΠΊΠ°ΡΠ΄ΠΈΠΎΠΌΠΈΠΎΠΏΠ°ΡΠΈΠ΅ΠΉ. ΠΠΎΠΊΠ°Π·Π°Π½ΠΎ, ΡΡΠΎ ΡΠ΅ΡΡΡΠΈΠΊΡΠΈΠ½ΠΎΠ΅ Π½Π°ΠΏΠΎΠ»Π½Π΅Π½ΠΈΠ΅ Π»Π΅Π²ΠΎΠ³ΠΎ ΠΆΠ΅Π»ΡΠ΄ΠΎΡΠΊΠ° Π½Π°Π±Π»ΡΠ΄Π°Π΅ΡΡΡ Π² ΠΎΡΠ½ΠΎΠ²Π½ΠΎΠΌ ΠΏΡΠΈ Π²ΡΡΠ°ΠΆΠ΅Π½Π½ΠΎΠΉ Π»Π΅Π³ΠΎΡΠ½ΠΎΠΉ Π³ΠΈΠΏΠ΅ΡΡΠ΅Π½Π·ΠΈΠΈ.The findings of echocardiography were used to reveal interrelation between the degree of pulmonary hypertension and severity of diastolic dysfunction of the left ventricle in patients with ischemic cardiomyopathy. Restrictive filling of the left ventricle is shown to be observed in marked pulmonary hypertension
Transcriptional profiling of macaque microglia reveals an evolutionary preserved gene expression program
Microglia are tissue-resident macrophages of the central nervous system (CNS), and important for CNS development and homeostasis. In the adult CNS, microglia monitor environmental changes and react to tissue damage, cellular debris, and pathogens. Here, we present a gene expression profile of purified microglia isolated from the rhesus macaque, a non-human primate, that consists of 666 transcripts. The macaque microglia transcriptome was intersected with the transcriptional programs of microglia from mouse, zebrafish, and human CNS tissues, to determine (dis)similarities. This revealed an extensive overlap of 342 genes between the transcriptional profile of macaque and human microglia, and showed that the gene expression profile of zebrafish is most distant when compared to other species. Furthermore, an evolutionair core based on the overlapping gene expression signature from all four species was identified. This study presents a macaque microglia transcriptomics profile, and identifies a gene expression program in microglia that is preserved across species, underscoring their CNS-tailored tissue macrophage functions as innate immune cells with CNS-surveilling properties
Distinct amyloid-beta and tau-associated microglia profiles in Alzheimer's disease
Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-beta and intraneuronal hyperphosphorylated tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-beta and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-beta plaques or both amyloid-beta plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-beta load and localized to amyloid-beta plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with overt tau pathology. This full characterization of human disease-associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies
Reproduction and recruitment of the brown shrimp Crangon crangon in the inner German Bight (North Sea): An interannual study and critical reappraisal
Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE
Drainage of central nervous system (CNS) antigens to the brain-draining cervical lymph nodes (CLN) is likely crucial in the initiation and control of autoimmune responses during multiple sclerosis (MS). We demonstrate neuronal antigens within CLN of MS patients. In monkeys and mice with experimental autoimmune encephalomyelitis (EAE) and in mouse models with non-inflammatory CNS damage, the type and extent of CNS damage was associated with the frequencies of CNS antigens within the cervical lymph nodes. In addition, CNS antigens drained to the spinal-cord-draining lumbar lymph nodes. In human MS CLN, neuronal antigens were present in pro-inflammatory antigen-presenting cells (APC), whereas the majority of myelin-containing cells were anti-inflammatory. This may reflect a different origin of the cells or different drainage mechanisms. Indeed, neuronal antigen-containing cells in human CLN did not express the lymph node homing receptor CCR7, whereas myelin antigen-containing cells in situ and in vitro did. Nevertheless, CLN from EAE-affected CCR7-deficient mice contained equal amounts of myelin and neuronal antigens as wild-type mice. We conclude that the type and frequencies of CNS antigens within the CLN are determined by the type and extent of CNS damage. Furthermore, the presence of myelin and neuronal antigens in functionally distinct APC populations within MS CLN suggests that differential immune responses can be evoked
Neuronal Chemokines: Versatile Messengers In Central Nervous System Cell Interaction
Whereas chemokines are well known for their ability to induce cell migration, only recently it became evident that chemokines also control a variety of other cell functions and are versatile messengers in the interaction between a diversity of cell types. In the central nervous system (CNS), chemokines are generally found under both physiological and pathological conditions. Whereas many reports describe chemokine expression in astrocytes and microglia and their role in the migration of leukocytes into the CNS, only few studies describe chemokine expression in neurons. Nevertheless, the expression of neuronal chemokines and the corresponding chemokine receptors in CNS cells under physiological and pathological conditions indicates that neuronal chemokines contribute to CNS cell interaction. In this study, we review recent studies describing neuronal chemokine expression and discuss potential roles of neuronal chemokines in neuronβastrocyte, neuronβmicroglia, and neuronβneuron interaction
- β¦