Neurons may be particularly sensitive to disruptions in transcription factor trafficking. Survival and injury signals must traverse dendrites or axons, in addition to soma, to affect nuclear ...transcriptional responses. Transcription factors exhibit continued nucleocytoplasmic shuttling; the predominant localization is regulated by binding to anchoring proteins that mask nuclear localization/export signals and/or target the factor for degradation. Two functional groups of karyopherins, importins and exportins, mediate RanGTPase-dependent transport through the nuclear pore. A growing number of recent studies, in Alzheimer, Parkinson, and Lewy body diseases, amyotrophic lateral sclerosis, and human immunodeficiency virus encephalitis, implicate aberrant cytoplasmic localization of transcription factors and their regulatory kinases in degenerating neurons. Potential mechanisms include impaired nuclear import, enhanced export, suppression of degradation, and sequestration in protein aggregates or organelles and may reflect unmasking of alternative cytoplasmic functions, both physiologic and pathologic. Some "nuclear" factors also function in mitochondria, and importins are also involved in axonal protein trafficking. Detrimental consequences of a decreased nuclear to cytoplasmic balance include suppression of neuroprotective transcription mediated by cAMP- and electrophile/antioxidant-response elements and gain of toxic cytoplasmic effects. Studying the pathophysiologic mechanisms regulating transcription factor localization should facilitate strategies to bypass deficits and restore adaptive neuroprotective transcriptional responses.
Recent advances indicate that maintaining a balanced level of autophagy is critically important for neuronal health and function. Pathologic dysregulation of macroautophagy has been implicated in ...synaptic dysfunction, cellular stress, and neuronal cell death. Autophagosomes and autolysosomes are induced in acute and chronic neurological disorders including stroke, brain trauma, neurotoxin injury, Parkinson's, Alzheimer's, Huntington's, motor neuron, prion, lysosomal storage, and other neurodegenerative diseases. Compared to other cell types, neuronal autophagy research presents particular challenges that may be addressed through still evolving techniques. Neuronal function depends upon maintenance of axons and dendrites (collectively known as neurites) that extend for great distances from the cell body. Both autophagy and mitochondrial content have been implicated in regulation of neurite length and function in physiological (plasticity) and pathological remodeling. Here, we highlight several molecular cell biological and imaging methods to study autophagy and mitophagy in neuritic and somatic compartments of differentiated neuronal cell lines and primary neuron cultures, using protocols developed in toxic and genetic models of parkinsonian neurodegeneration. In addition, mature neurons can be studied using in vivo protocols for modeling ischemic and traumatic injuries. Future challenges include application of automated computer-assisted image analysis to the axodendritic tree of individual neurons and improving methods for measuring neuronal autophagic flux.
Abstract We present two cases of tumefactive demyelination (TD) occurring in close association with a developmental venous anomaly (DVA). Our purpose is to describe the association between ...demyelinating lesions and venous anomalies, as only one case of TD associated with a DVA has been published in the literature. Appropriate recognition of this “do not touch” lesion may avoid invasive and potentially harmful procedures such as biopsy or resection.
Tectal pineal cyst in a 1-year-old girl Plowey, Edward D., MD, PhD; Vogel, Hannes, MD; Yeom, Kristen W., MD ...
Human pathology,
03/2014, Letnik:
45, Številka:
3
Journal Article
Recenzirano
Summary Glial cysts of the pineal gland can frequently be found in adults and children, but only rarely do they enlarge to become clinically relevant. We report a unique presentation of a pineal cyst ...in the midbrain tectum of a 16-month-old girl who initially presented with ptosis and strabismus. Preoperative imaging studies and intraoperative findings revealed no continuity between the tectal cyst and the pineal gland proper. We surmise that this tectal pineal cyst may have arisen from duplicated pineal gland tissue.
Transthyretin/TTR gene mutations usually cause systemic amyloidotic diseases. Few TTR variants preferentially affect the central nervous system, manifesting as oculoleptomeningeal amyloidosis. ...Patients with TTR meningovascular amyloidosis often show dementia, however the neuropathologic features of dementia in these cases have not been elucidated. We report the neuropathologic findings from a brain autopsy of a 72-year-old man with the rare Tyr69His (Y69H) TTR gene variant, dementia and ataxia. Severe amyloid deposits were observed in the leptomeninges and in a subpial and subependymal distribution. Mass spectrometry analysis demonstrated that the amyloid deposits were comprised of over 80 % of the variant TTR. TTR was undetectable by mass spectrometry in the neocortex subjacent to the subpial amyloid deposits. Subpial TTR amyloid deposits were associated with brisk superficial reactive gliosis and siderosis in the neocortex and cerebellar cortex. Subependymal TTR amyloid deposits were associated with subjacent myelin pallor in the hippocampal outflow tract structures including the alveus, fimbria and fornix. Phospho-tau immunostains demonstrated transentorhinal-stage neurofibrillary degeneration (Braak stage II) which, in the absence of neocortical amyloid-beta and neuritic plaques, was indicative of primary age-related tauopathy (PART). However, distinctive phospho-tau aggregates were observed subjacent to the subpial TTR amyloid deposits in all regions of the neocortex, including the primary motor and striate cortices, suggesting a potential link between TTR amyloid and neocortical tauopathy. Our report reveals novel insights into the potential neuropathologic substrates of dementia in variant TTR amyloidosis that need to be investigated in larger autopsy series.
Background: Cerebral cavernous malformations (CCMs) are angiographically occult vascular malformations of the central nervous system. As a result of hemorrhage and mass effect, patients may present ...with focal neurologic deficits, seizures, and other symptoms necessitating treatment. Once symptomatic, most often from hemorrhage, CCMs are treated with microsurgical resection. Orbital cavernous hemangiomas (OCHs) are similar but distinct vascular malformations that present within the orbital cavity. Even though CCMs and OCHs are both marked by dilated endothelial-lined vascular channels, they are infrequently seen in the same patient. Case Description: We provide a brief overview of the two related pathologies in the context of a patient presenting to our care with concomitant lesions, which were both resected in full without complication. Conclusion: This is the first known report that describes a case of concomitant CCM and OCH and explores the origins of two pathologies that are rarely encountered together in neurosurgical practice. Recognition of disparate symptomatologies is important for properly managing these patients.
Recently, physical exercise has been shown to significantly alter neurochemistry and neuronal function and to increase neurogenesis in discrete brain regions. Although we have documented that ...physical exercise leads to molecular changes in the posterior hypothalamic area (PHA), the impact on neuronal activity is unknown. The purpose of the present study was to determine whether neuronal activity in the PHA is altered by physical exercise. Spontaneously hypertensive rats (SHR) were allowed free access to running wheels for a period of 10 wk (exercised group) or no wheel access at all (nonexercised group). Single-unit extracellular recordings were made in anesthetized in vivo whole animal preparations or in vitro brain slice preparations. The spontaneous firing rates of PHA neurons in exercised SHR in vivo were significantly lower (8.5 +/- 1.6 Hz, n = 31 neurons) compared with that of nonexercised SHR in vivo (13.7 +/- 1.8 Hz, n = 38 neurons; P < 0.05). In addition, PHA neurons that possessed a cardiac-related rhythm in exercised SHR fired significantly lower (6.0 +/- 1.8 Hz, n = 11 neurons) compared with nonexercised SHR (12.1 +/- 2.4 Hz, n = 18 neurons; P < 0.05). Similarly, the spontaneous in vitro firing rates of PHA neurons from exercised SHR were significantly lower (3.5 +/- 0.3 Hz, n = 67 neurons) compared with those of nonexercised SHR (5.6 +/- 0.5 Hz, n = 58 neurons; P < 0.001). Both the in vivo and in vitro findings support the hypothesis that physical exercise can lower spontaneous activity of neurons in a cardiovascular regulatory region of the brain. Thus physical exercise may alter central neural control of cardiovascular function by inducing lasting changes in neuronal activity.
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