Dysregulation of long interspersed nuclear element 1 (LINE-1, L1), a dominant class of transposable elements in the human genome, has been linked to neurodegenerative diseases, but whether elevated ...L1 expression is sufficient to cause neurodegeneration has not been directly tested. Here, we show that the cerebellar expression of L1 is significantly elevated in ataxia telangiectasia patients and strongly anti-correlated with the expression of epigenetic silencers. To examine the role of L1 in the disease etiology, we developed an approach for direct targeting of the L1 promoter for overexpression in mice. We demonstrated that L1 activation in the cerebellum led to Purkinje cell dysfunctions and degeneration and was sufficient to cause ataxia. Treatment with a nucleoside reverse transcriptase inhibitor blunted ataxia progression by reducing DNA damage, attenuating gliosis, and reversing deficits of molecular regulators for calcium homeostasis in Purkinje cells. Our study provides the first direct evidence that L1 activation can drive neurodegeneration.
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•LINE-1 is significantly upregulated in ataxia telangiectasia patients’ cerebella•Targeted activation of LINE-1 in cerebellar Purkinje cells in mice caused ataxia•Purkinje cells in diseased mice showed prominent signs of ER stress and DNA damage•Treatment with reverse transcriptase inhibitor attenuated disease progression
Takahashi et al. found elevated expression of the transposable element LINE-1 in the cerebella of ataxia telangiectasia patients. A mouse model in which LINE-1 is activated in cerebellar Purkinje neurons showed significant ataxia with neurodegeneration and electrophysical abnormalities. The progression of the ataxia was attenuated with a reverse transcriptase inhibitor treatment.
Since their discovery decades ago, the primary physiological and pathological effects of potassium channels have been attributed to their ion conductance, which sets membrane potential and ...repolarizes action potentials. For example, Kv3 family channels regulate neurotransmitter release by repolarizing action potentials. Here we report a surprising but crucial function independent of potassium conductance: by organizing the F-actin cytoskeleton in mouse nerve terminals, the Kv3.3 protein facilitates slow endocytosis, rapid endocytosis, vesicle mobilization to the readily releasable pool, and recovery of synaptic depression during repetitive firing. A channel mutation that causes spinocerebellar ataxia inhibits endocytosis, vesicle mobilization, and synaptic transmission during repetitive firing by disrupting the ability of the channel to nucleate F-actin. These results unmask novel functions of potassium channels in endocytosis and vesicle mobilization crucial for sustaining synaptic transmission during repetitive firing. Potassium channel mutations that impair these “non-conducting” functions may thus contribute to generation of diverse neurological disorders.
•Kv3.3 channel facilitates slow and rapid endocytosis by nucleating F-actin at synapse•Kv3.3 channel facilitates vesicle mobilization and recovery of short-term depression•Linking Kv3.3-related spinocerebellar ataxia to endocytosis and vesicle mobilization•Kv3.3 non-conductive functions are crucial for synaptic functions and disorders
Wu et al. found that Kv3.3 potassium channels facilitate endocytosis, vesicle mobilization, and recovery of short-term synaptic depression by organizing the presynaptic F-actin cytoskeleton. These “non-conductive” functions are impaired by a Kv3.3 mutation that causes spinocerebellar ataxia. Thus, by nucleating F-actin, Kv3.3 is crucial for endocytosis, synaptic transmission, and neurological disorders.
Despite the known causality of copy-number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each gene’s contribution to the constellation of neural phenotypes remain ...elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered that mitochondrial dysfunction participates in WS pathogenesis. Dysfunction is facilitated in part by the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP-synthase machinery. Removal of Dnajc30 in mice resulted in hypofunctional mitochondria, diminished morphological features of neocortical pyramidal neurons, and altered behaviors reminiscent of WS. The mitochondrial features are consistent with our observations of decreased integrity of oxidative phosphorylation supercomplexes and ATP-synthase dimers in WS. Thus, we identify DNAJC30 as an auxiliary component of ATP-synthase machinery and reveal mitochondrial maladies as underlying certain defects in brain development and function associated with WS.
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•Systems biology analyses reveal mitochondrial contribution to 7q11.23 CNV syndromes•The 7q11.23 protein DNAJC30 facilitates ATP synthesis in neocortical neurons•Altered behavior and mitochondrial and neuronal physiomorphology in Dnajc30−/− mice•Deficient mitochondrial function and OXPHOS architecture in WS cells and brains
Reduced copy number of DNAJC30, now shown to interact with the mitochondrial ATP synthase, leads to mitochondrial dysfunction underlying neuronal defects in Williams syndrome.
Exposure measurement data from several developed countries indicate that human beings are widely exposed to low levels of the synthetic xenoestrogen, bisphenol A. We reported previously that ...bisphenol A, even at doses below the reference safe daily limit for human exposure, recommended by the U.S. Environmental Protection Agency, impairs the synaptogenic response to 17β-estradiol in the hippocampus of ovariectomized rats. Recent experiments revealed that bisphenol A also interferes with androgen receptor-mediated transcriptional activities. Thus, to investigate whether bisphenol A impairs synaptogenesis in the medial prefrontal cortex (mPFC) and hippocampus of adult male rats, castrated and sham-operated animals were treated with different combinations of bisphenol A (300 μg/kg), testosterone propionate (1.5 mg/kg), and sesame oil vehicle. The brains were processed for electron microscopic stereology, and the number of asymmetric spine synapses in the mPFC and CA1 hippocampal area was estimated. In both regions analyzed, bisphenol A reduced the number of spine synapses in sham-operated, gonadally intact animals, which was accompanied by a compensatory increase in astroglia process density. In addition, bisphenol A prevented both the prefrontal and hippocampal synaptogenic response to testosterone supplementation in castrated males. These results demonstrate that bisphenol A interferes with the synaptogenic response to testosterone in the mPFC and hippocampus of adult male rats. Because the hippocampal synaptogenic action of androgens seems to be independent of androgen and estrogen receptors in males, the potential mechanisms that underlie these negative effects of bisphenol A remain the subject of further investigation.
SARS–CoV-2 infection of the placenta Hosier, Hillary; Farhadian, Shelli F; Morotti, Raffaella A ...
The Journal of clinical investigation,
09/2020, Letnik:
130, Številka:
9
Journal Article
Recenzirano
BACKGROUND. The effects of the novel coronavirus disease 2019 (COVID-19) in pregnancy remain relatively unknown. We present a case of second trimester pregnancy with symptomatic COVID-19 complicated ...by severe preeclampsia and placental abruption. METHODS. We analyzed the placenta for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through molecular and immunohistochemical assays and by and electron microscopy and measured the maternal antibody response in the blood to this infection. RESULTS. SARS-CoV-2 localized predominantly to syncytiotrophoblast cells at the materno-fetal interface of the placenta. Histological examination of the placenta revealed a dense macrophage infiltrate, but no evidence for the vasculopathy typically associated with preeclampsia. CONCLUSION. This case demonstrates SARS-CoV-2 invasion of the placenta, highlighting the potential for severe morbidity among pregnant women with COVID-19. FUNDING. Beatrice Kleinberg Neuwirth Fund and Fast Grant Emergent Ventures funding from the Mercatus Center at George Mason University. The funding bodies did not have roles in the design of the study or data collection, analysis, and interpretation and played no role in writing the manuscript.
SARS-CoV-2 infection of the placenta Hosier, Hillary; Farhadian, Shelli F; Morotti, Raffaella A ...
The Journal of clinical investigation,
09/2020, Letnik:
130, Številka:
9
Journal Article
Recenzirano
FUNDING. Beatrice Kleinberg Neuwirth Fund and Fast Grant Emergent Ventures funding from the Mercatus Center at George Mason University. The funding bodies did not have roles in the design of the ...study or data collection, analysis, and interpretation and played no role in writing the manuscript.
Despite the known causality of copy number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each genes’ contribution to the constellation of neural phenotypes remains ...elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered mitochondrial dysfunction participates in WS pathogenesis. Dysfunction is facilitated in part by the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP synthase machinery. Removal of
Dnajc30
in mice resulted in hypofunctional mitochondria, diminished morphological features of neocortical pyramidal neurons, and altered behaviors reminiscent of WS. The mitochondrial features are consistent with the decreased integrity of oxidative phosphorylation supercomplexes and ATP synthase dimers we observed in WS. Thus, we reveal DNAJC30 as a novel auxiliary component of ATP synthase machinery, and link mitochondrial maladies as underlying certain defects in brain development and function associated with WS.
Background Despite the fact that women are twice as likely to develop depression as men, our understanding of depression neurobiology in female subjects is limited. We have recently reported in male ...rats that development of helpless behavior is associated with a severe loss of hippocampal spine synapses, which is reversed by treatment with the antidepressant desipramine. Considering that estradiol has a hippocampal synaptogenic effect similar to those of antidepressants, the presence of estradiol during the female reproductive life might influence behavioral and synaptic responses to stress and depression. Methods With electron microscopic stereology, we analyzed hippocampal spine synapses in association with helpless behavior in ovariectomized female rats ( n = 70), under different conditions of estradiol exposure. Results Stress induced an acute and persistent loss of hippocampal spine synapses, whereas subchronic treatment with desipramine reversed the stress-induced synaptic loss. Estradiol supplementation given either before stress or before escape testing of nonstressed animals increased the number of hippocampal spine synapses. Correlation analysis demonstrated a statistically significant negative correlation between the severity of helpless behavior and hippocampal spine synapse numbers. Conclusions These findings suggest that hippocampal spine synapse remodeling might be a critical factor underlying learned helplessness and, possibly, the neurobiology of depression.
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