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Cell Reports Jan 2024While ATM loss of function has long been identified as the genetic cause of ataxia-telangiectasia (A-T), how it leads to selective and progressive degeneration of...
While ATM loss of function has long been identified as the genetic cause of ataxia-telangiectasia (A-T), how it leads to selective and progressive degeneration of cerebellar Purkinje and granule neurons remains unclear. ATM expression is enriched in microglia throughout cerebellar development and adulthood. Here, we find evidence of microglial inflammation in the cerebellum of patients with A-T using single-nucleus RNA sequencing. Pseudotime analysis revealed that activation of A-T microglia preceded upregulation of apoptosis-related genes in granule and Purkinje neurons and that microglia exhibited increased neurotoxic cytokine signaling to granule and Purkinje neurons in A-T. To confirm these findings experimentally, we performed transcriptomic profiling of A-T induced pluripotent stem cell (iPSC)-derived microglia, which revealed cell-intrinsic microglial activation of cytokine production and innate immune response pathways compared to controls. Furthermore, A-T microglia co-culture with either control or A-T iPSC-derived neurons was sufficient to induce cytotoxicity. Taken together, these studies reveal that cell-intrinsic microglial activation may promote neurodegeneration in A-T.
Topics: Humans; Ataxia Telangiectasia; Microglia; Ataxia Telangiectasia Mutated Proteins; Neurons; Cytokines
PubMed: 38159274
DOI: 10.1016/j.celrep.2023.113622 -
Biophysical Journal Dec 2023Discovered just over 25 years ago in cerebellar Purkinje neurons, resurgent Na current was originally described operationally as a component of voltage-gated Na current... (Review)
Review
Discovered just over 25 years ago in cerebellar Purkinje neurons, resurgent Na current was originally described operationally as a component of voltage-gated Na current that flows upon repolarization from relatively depolarized potentials and speeds recovery from inactivation, increasing excitability. Its presence in many excitable cells and absence from others has raised questions regarding its biophysical and molecular mechanisms. Early studies proposed that Na channels capable of generating resurgent current are subject to a rapid open-channel block by an endogenous blocking protein, which binds upon depolarization and unblocks upon repolarization. Since the time that this mechanism was suggested, many physiological and structural studies of both Na and K channels have revealed aspects of gating and conformational states that provide insights into resurgent current. These include descriptions of domain movements for activation and inactivation, solution of cryo-EM structures with pore-blocking compounds, and identification of native blocking domains, proteins, and modulatory subunits. Such results not only allow the open-channel block hypothesis to be refined but also link it more clearly to research that preceded it. This review considers possible mechanisms for resurgent Na current in the context of earlier and later studies of ion channels and suggests a framework for future research.
PubMed: 38130058
DOI: 10.1016/j.bpj.2023.12.016 -
Journal of Neuropathology and... Jan 2024Cerebellar amyloid-β (Aβ) plaques are a component of the diagnostic criteria used in Thal staging and ABC scoring for Alzheimer disease (AD) neuropathologic change....
Cerebellar amyloid-β (Aβ) plaques are a component of the diagnostic criteria used in Thal staging and ABC scoring for Alzheimer disease (AD) neuropathologic change. However, Aβ deposits in this anatomic compartment are unique and under-characterized; and their relationship with other pathological findings are largely undefined. In 73 cases of pure or mixed AD with an A3 score in the ABC criteria, parenchymal (plaques) and vascular (cerebral amyloid angiopathy [CAA]) cerebellar Aβ-42 deposits were characterized with respect to localization, morphology, density, and intensity. Over 85% of cases demonstrated cerebellar Aβ-42 parenchymal staining that correlated with a Braak stage V-VI/B3 score (p < 0.01). Among the 63 with cerebellar Aβ-42 deposits, a diffuse morphology was observed in 75% of cases, compact without a central dense core in 32%, and compact with a central dense core in 16% (all corresponding to plaques evident on hematoxylin and eosin staining). Cases with Purkinje cell (PC) loss showed higher proportions of PC layer Aβ-42 staining than cases without PC loss (88% vs 44%, p = 0.02), suggesting a link between Aβ-42 deposition and PC damage. Among all 73 cases, CAA was observed in the parenchymal vessels of 19% of cases and in leptomeningeal vessels in 44% of cases.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Cerebral Amyloid Angiopathy; Cerebellum; Plaque, Amyloid; Brain
PubMed: 38114098
DOI: 10.1093/jnen/nlad107 -
Neuroreport Feb 2024The mechanism by which α2-adrenergic receptors (ARs) modulate the cerebellar parallel fiber-Purkinje cell (PF-PC) synaptic transmission is unclear. We investigated this...
The mechanism by which α2-adrenergic receptors (ARs) modulate the cerebellar parallel fiber-Purkinje cell (PF-PC) synaptic transmission is unclear. We investigated this issue using electrophysiological and neuropharmacological methods. Six- to eight-week-old ICR mice were used in the study. Under in vivo conditions, PF-PC synaptic transmission was evoked by facial stimulation of ipsilateral whisker pad, and recorded using cell-attached patch from PCs. Under in-vitro conditions, PF-PC synaptic transmission was evoked by electrical stimulation of the molecular layer in cerebellar slices, and was recorded using whole-cell recording from PCs. SR95531 (20 µM) was added to the ACSF during all recordings to prevent GABAA receptor-mediated inhibition. Air-puff stimulation of the ipsilateral whisker pad in-vivo evoked simple spike (eSS) firing of cerebellar PCs. Microapplication of noradrenaline (15 µM) to the molecular layer significantly decreased the numbers and frequency of eSS, an effect abolished by the α2-AR antagonist. Microapplication of an α2-AR agonist, UK14304 (1 µM), significantly decreased the numbers of eSS in PCs, which was abolished by either α2A- or α2B-AR antagonist, but not by α2C-AR antagonist. Under in-vitro conditions, application of UK 14304 significantly decreased the amplitude of PF-PC EPSCs and increased the paired-pulse ratio, which were abolished by either α2A- or α2B-AR antagonist. The present results indicate that activation of presynaptic α2A- and α2B-AR downregulates PF-PC synaptic transmission in mouse cerebellar cortex.
Topics: Animals; Mice; Purkinje Cells; Mice, Inbred ICR; Cerebellar Cortex; Cerebellum; Synaptic Transmission
PubMed: 38109417
DOI: 10.1097/WNR.0000000000001983 -
Cell Reports Dec 2023Patients with Rett syndrome suffer from a loss-of-function mutation of the Mecp2 gene, which results in various symptoms including autistic traits and motor deficits....
Patients with Rett syndrome suffer from a loss-of-function mutation of the Mecp2 gene, which results in various symptoms including autistic traits and motor deficits. Deletion of Mecp2 in the brain mimics part of these symptoms, but the specific function of methyl-CpG-binding protein 2 (MeCP2) in the cerebellum remains to be elucidated. Here, we demonstrate that Mecp2 deletion in Purkinje cells (PCs) reduces their intrinsic excitability through a signaling pathway comprising the small-conductance calcium-activated potassium channel PTP1B and TrkB, the receptor of brain-derived neurotrophic factor. Aberration of this cascade, in turn, leads to autistic-like behaviors as well as reduced vestibulocerebellar motor learning. Interestingly, increasing activity of TrkB in PCs is sufficient to rescue PC dysfunction and abnormal motor and non-motor behaviors caused by Mecp2 deficiency. Our findings highlight how PC dysfunction may contribute to Rett syndrome, providing insight into the underlying mechanism and paving the way for rational therapeutic designs.
Topics: Humans; Animals; Methyl-CpG-Binding Protein 2; Rett Syndrome; Purkinje Cells; Autistic Disorder; Signal Transduction; Disease Models, Animal
PubMed: 38100348
DOI: 10.1016/j.celrep.2023.113559 -
Annals of Clinical and Translational... Feb 2024Postmortem examination of the essential tremor cerebellum has revealed a variety of pathological changes centered in and around Purkinje cells. Studies have...
OBJECTIVE
Postmortem examination of the essential tremor cerebellum has revealed a variety of pathological changes centered in and around Purkinje cells. Studies have predominantly focused on cerebellar neuronal connections. Bergmann glial morphology has not yet been studied in essential tremor. Among their many roles, Bergmann glia in the cerebellar cortex ensheath Purkinje cell synapses and provide neuroprotection. Specifically, the complex radial processes and lateral appendages of Bergmann glia are structural domains that modulate Purkinje cell synaptic transmission. In this study, we investigate whether Bergmann glia morphology is altered in the essential tremor cerebellum.
METHODS
We applied the Golgi-Kopsch method and used computerized three-dimensional cell reconstruction to visualize Bergmann glia in the postmortem cerebellum of 34 cases and 17 controls. We quantified morphology of terminal structures (number of terminations and lateral appendage density) and morphology of radial processes (total process length, branch length, branch order, and branch volume) in each glial cell. We quantified number of branches and volume as well.
RESULTS
Essential tremor cases had a 31.9% decrease in process terminations and a 35.7% decrease in lateral appendage density in Bergmann glia. Total process length and branch length did not differ between essential tremor cases and controls. We found also a reduction in number of secondary and tertiary branches and tertiary branches volume.
INTERPRETATION
These findings suggest that Bergmann glia in essential tremor cases have more alterations in their terminal structures, with a relative preservation of radial processes, and highlight a potential role for these astrocytes in the disease pathophysiology.
Topics: Humans; Essential Tremor; Neuroglia; Purkinje Cells; Astrocytes; Cerebellum
PubMed: 38098226
DOI: 10.1002/acn3.51958 -
ELife Dec 2023Spinocerebellar ataxia type 6 (SCA6) is a rare disease that is characterized by cerebellar dysfunction. Patients have progressive motor coordination impairment, and...
Spinocerebellar ataxia type 6 (SCA6) is a rare disease that is characterized by cerebellar dysfunction. Patients have progressive motor coordination impairment, and postmortem brain tissue reveals degeneration of cerebellar Purkinje cells and a reduced level of cerebellar brain-derived neurotrophic factor (BDNF). However, the pathophysiological changes underlying SCA6 are not fully understood. We carried out RNA-sequencing of cerebellar vermis tissue in a mouse model of SCA6, which revealed widespread dysregulation of genes associated with the endo-lysosomal system. Since disruption to endosomes or lysosomes could contribute to cellular deficits, we examined the endo-lysosomal system in SCA6. We identified alterations in multiple endosomal compartments in the Purkinje cells of SCA6 mice. Early endosomes were enlarged, while the size of the late endosome compartment was reduced. We also found evidence for impaired trafficking of cargo to the lysosomes. As the proper functioning of the endo-lysosomal system is crucial for the sorting and trafficking of signaling molecules, we wondered whether these changes could contribute to previously identified deficits in signaling by BDNF and its receptor tropomyosin kinase B (TrkB) in SCA6. Indeed, we found that the enlarged early endosomes in SCA6 mice accumulated both BDNF and TrkB. Furthermore, TrkB recycling to the cell membrane in recycling endosomes was reduced, and the late endosome transport of BDNF for degradation was impaired. Therefore, mis-trafficking due to aberrant endo-lysosomal transport and function could contribute to SCA6 pathophysiology through alterations to BDNF-TrkB signaling, as well as mishandling of other signaling molecules. Deficits in early endosomes and BDNF localization were rescued by chronic administration of a TrkB agonist, 7,8-dihydroxyflavone, that we have previously shown restores motor coordination and cerebellar TrkB expression. The endo-lysosomal system is thus both a novel locus of pathophysiology in SCA6 and a promising therapeutic target.
Topics: Humans; Mice; Animals; Brain-Derived Neurotrophic Factor; Spinocerebellar Ataxias; Cerebellum; Endosomes; Purkinje Cells; Receptor, trkB
PubMed: 38084749
DOI: 10.7554/eLife.90510 -
Environment International Jan 2024Diesel exhaust particulate matter (DEPM) are important components of urban air pollution worldwide. Recent studies proved that airborne DEPM can enter the human brain,...
Diesel exhaust particulate matter (DEPM) are important components of urban air pollution worldwide. Recent studies proved that airborne DEPM can enter the human brain, which was associated with brain and mental diseases. In this study, we investigated the effects of DEPM exposure on behavior, and explored potential mechanisms from the perspective of metabolism in specific brain regions and short chain fatty acids (SCFAs) in the gut using mice. The results showed that inhalation of DEPM induced locomotor hyperactivity and a tendency for memory decline in mice. Exposure to DEPM disrupted motor behavior generation related cerebellar Purkinje cells, induced widespread reduction of neurotransmitters in the frontal cortex, and downregulated expression of genes encoding Brain-derived neurotrophic factor (BDNF) and involved in the Brain-blood-barrier (BBB) in the hippocampus. Moreover, there was a DEPM dose-dependent increase in fecal SCFA levels. Correlation analysis showed that DEPM-induced locomotor hyperactivity was mainly associated with decreased neurotransmission in the frontal cortex and increased gut SCFAs, and those associations were discussed. This study provides new insights into the mechanisms underpinning behavioral changes caused by air pollution, and extends our knowledge on the toxicity and health effects of airborne pollutants.
Topics: Humans; Animals; Mice; Air Pollutants; Vehicle Emissions; Particulate Matter; Brain; Blood-Brain Barrier; Inhalation Exposure
PubMed: 38056096
DOI: 10.1016/j.envint.2023.108359 -
Ideggyogyaszati Szemle Nov 2023
Although serum anti-neuronal antibodies are found in acute ischemic stroke (AIS) patients, it is not completely clear whether they are already present before the...
BACKGROUND AND PURPOSE
Although serum anti-neuronal antibodies are found in acute ischemic stroke (AIS) patients, it is not completely clear whether they are already present before the cerebrovascular event or emerge thereafter.
.METHODS
Sera of 21 consecutive first-ever AIS patients were collected within the first day of AIS (baseline), as well as 1 and 6 months after AIS. Well-characterized and novel anti-neuronal antibodies were investigated by cell-based assays, immunoblotting and indirect immunohistochemistry.
.RESULTS
None of the AIS sera collected at different time points showed well-characterized antibodies. In 7 patients, 1- and 6-month sera (but not baseline sera) showed IgG mostly reacting with soma and dendrites of cerebellar Purkinje cells. Antibody-positive patients did not differ in terms of clinical and etiological features.
.CONCLUSION
Our results provide evidence for the antibody-triggering action of AIS. Although anti-cerebellar antibodies are not associated with the severity of stroke, they may potentially contribute to chronic post-stroke complications and disability.
.Topics: Humans; Ischemic Stroke; Stroke; Cerebellum; Brain Ischemia
PubMed: 38051689
DOI: 10.18071/isz.76.0394 -
Cell Reports Dec 2023Cerebellar dysfunction has been linked to autism spectrum disorders (ASDs). Although cerebellar pathology has been observed in individuals with fragile X syndrome (FXS)...
Cerebellar dysfunction has been linked to autism spectrum disorders (ASDs). Although cerebellar pathology has been observed in individuals with fragile X syndrome (FXS) and in mouse models of the disorder, a cerebellar functional contribution to ASD-relevant behaviors in FXS has yet to be fully characterized. In this study, we demonstrate a critical cerebellar role for Fmr1 (fragile X messenger ribonucleoprotein 1) in ASD-relevant behaviors. First, we identify reduced social behaviors, sensory hypersensitivity, and cerebellar dysfunction, with loss of cerebellar Fmr1. We then demonstrate that cerebellar-specific expression of Fmr1 is sufficient to impact social, sensory, cerebellar dysfunction, and cerebro-cortical hyperexcitability phenotypes observed in global Fmr1 mutants. Moreover, we demonstrate that targeting the ASD-implicated cerebellar region Crus1 ameliorates behaviors in both cerebellar-specific and global Fmr1 mutants. Together, these results demonstrate a critical role for the cerebellar contribution to FXS-related behaviors, with implications for future therapeutic strategies.
Topics: Animals; Mice; Fragile X Syndrome; Autistic Disorder; Fragile X Mental Retardation Protein; Autism Spectrum Disorder; Disease Models, Animal; Cerebellar Diseases; Mice, Knockout
PubMed: 38048226
DOI: 10.1016/j.celrep.2023.113533