1,720,987 research outputs found
Cyclin-dependent kinase 5 (CDK5) and neuronal cell death
No full textMany neurological disorders like Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis (ALS) or stroke have in common a definite loss of CNS neurons due to apoptotic or necrotic neuronal cell death. Previous studies suggested that proapoptotic stimuli may trigger an abortive and, therefore, eventually fatal cell cycle reentry in postmitotic neurons. Neuroprotective effects of small molecule inhibitors of cyclin-dependent kinases (CDKs), which are key regulators of cell cycle progression, support the cell cycle theory of neuronal apoptosis. However, growing evidence suggests that deregulated CDK5, which is not involved in cell cycle control, rather than cell cycle relevant members of the CDK family, promotes neuronal cell death. Here we summarize the current knowledge about the involvement of CDK5 in neuronal cell death and discuss possible up- or downstream partners of CDK5. Moreover, we discuss potential therapeutic options that might arise from the identification of CDK5 as an important upstream element of neuronal cell death cascades
Kir channels in the CNS: emerging new roles and implications for neurological diseases
No full textInwardly rectifying potassium (Kir) channels have long been regarded as transmembrane proteins that regulate the membrane potential of neurons and that are responsible for [K+] siphoning in glial cells. The subunit diversity within the Kir channel family is growing rapidly and this is reflected in the multitude of roles that Kir channels play in the central nervous system (CNS). Kir channels are known to control cell differentiation, modify CNS hormone secretion, modulate neurotransmitter release in the nigrostriatal system, may act as hypoxia-sensors and regulate cerebral artery dilatation. The increasing availability of genetic mouse models that express inactive Kir channel subunits has opened new insights into their role in developing and adult mammalian tissues and during the course of CNS disorders. New aspects with respect to the role of Kir channels during CNS cell differentiation and neurogenesis are also emerging. Dysfunction of Kir channels in animal models can lead to severe phenotypes ranging from early postnatal death to an increased susceptibility to develop epileptic seizures. In this review, we summarize the in vivo data that demonstrate the role of Kir channels in regulating morphogenetic events, such as the proliferation, differentiation and survival of neurons and glial cells. We describe the way in which the gating of Kir channel subunits plays an important role in polygenic CNS diseases, such as white matter disease, epilepsy and Parkinson's disease
Time-lapse 2-photon laser imaging to study microglia dynamics in the SOD1-mouse model of ALS
No full textHereditary motor and sensory neuropathy caused by a novel mutation in LITAF
No full textHereditary motor-sensory neuropathy (HMSN) Type 1/CMT 1 is a disorder of the peripheral nervous System. The underlying genetic cause is heterogeneous, and mutations in LITAF (Lipopolysaccharide-induced TNF-alpha factor) represent a rare cause of CMT Type 1. In this report, a novel missense mutation is presented in the LITAF gene (c.430G > A p.V144M) in a German CMT family exhibiting typical electrophysiological features of a demyelinating neuropathy with conduction blocks and variable age at onset. Molecular genetic characterization of demyelinating HMSN should therefore include screening of the LITAF gene if typical signs of a non-homogenous demyelinating neuropathy combined with dominant familial occurrence are evident. (c) 2009 Elsevier B.V. All rights reserved
Time-lapse 2-photon laser imaging to study microglia dynamics in the SOD1-mouse model of ALS
No full textGlia cells in amyotrophic lateral sclerosis: New clues to understanding an old disease?
No full textIn classic neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), the pathogenic concept of a cell-autonomous disease of motor neurons has been challenged increasingly in recent years. Macro- and microglial cells have come to the forefront for their role in multistep degenerative processes in ALS and respective disease models. The activation of astroglial and microglial cells occurs early in the pathogenesis of the disease and seems to greatly influence disease onset and promotion. The role of oligodendrocytes and Schwann cells remains elusive. In this review we highlight the impact of nonneuronal cells in ALS pathology. We discuss diverse glial membrane proteins that are necessary to control neuronal activity and neuronal cell survival, and summarize the contribution of these proteins to motor neuron death in ALS. We also describe recently discovered glial mechanisms that promote motor neuron degeneration using state-of-the-art genetic mouse technology. Finally, we provide an outlook on the extent to which these new pathomechanistic insights may offer novel therapeutic approaches
Late-onset myopathy of the posterior calf muscles mimicking Miyoshi myopathy unrelated to dysferlin mutation: a case report
Full text linkIntroduction
Miyoshi myopathy, a type of distal myopathy with predominant involvement of the posterior calf muscles, has been assigned to mutations in the dysferlin gene. However, many of the late-onset limb-girdle and distal myopathies that resemble dysferlinopathy or Miyoshi myopathy remain unclassified, even after extensive immunohistological and genetic analysis.
Case presentation
We report the case of a 59-year-old Caucasian man with distal myopathy and exercise-induced myalgia, preferentially of the leg muscles, closely resembling the Miyoshi phenotype. Magnetic resonance imaging of his calf muscles showed typical fatty replacement of the medial heads of the gastrocnemius muscles and soleus muscles, with progression to the adductor longus muscles over a time course of two years. However, genetic analysis revealed that the phenotype of our patient was not related to a mutation in the dysferlin gene but to a novel homozygous splice mutation in the anoctamin 5 gene. Mutations in the anoctamin 5 gene have so far been identified only in some cases of limb-girdle and distal myopathy. Mutations in the anoctamin 5 gene have been assigned to limb-girdle muscular dystrophy type 2L, while distal Miyoshi-like phenotypes have been classified as Miyoshi myopathy type 3.
Conclusion
The case presented in this report further strengthens the underlying genetic heterogeneity in Miyoshi myopathy-like phenotypes and adds another family to non-dysferlin, Miyoshi myopathy type 3 of late-onset. Furthermore, our case supports the recent observation that anoctamin 5 mutations are a primary cause of distal non-dysferlin myopathies. Therefore, given the increasing number of anoctamin 5 mutations in Miyoshi-like phenotypes, genetic analysis should include an anoctamin 5 screen in late-onset limb-girdle and distal myopathies
Calcium influx mediated by the inwardly rectifying K+ channel Kir4.1 (KCNJ10) at low external K+ concentration
No full textCOS-1 cells with heterologeous expression of the Kir4.1 (KCNJ10) channel subunit, possess functional Kir4.1 channels and become capable to generating cytosolic Ca2+ transients, upon lowering of the extracellular K+ concentration to 2 mM or below. These Ca2+ transients are blocked by external Ba2+ (100 mu M). Acute brain stem slices from wild-type mice (second post-natal week), which were loaded with the fluorescent Ca2+ indicator Oregon Green BAPTA-1-AM, were exposed to 0.2 mM K+. Under these conditions astrocytes, but not neurons, responded with cytosolic Ca2+ elevations in wild-type mice. This astrocyte-specific response has previously been used to identify astroglial cells type [R. Dallwig, H. Vitten, J.W. Deitmer, A novel barium- sensitive calcium influx into rat astrocytes at low external potassium. Cell Calcium 28 (2000) 247-259]. In Kir4.1 knock-out (Kir4. 1(-/-)) mice, the number of responding cells was dramatically reduced and the Ca2+ transients in responding cells were significantly smaller than in wild-type mice. Our results indicate that Kir4.1 channels are the molecular substrate for the observed Ca2+ influx in astrocytes under (c) 2007 Elsevier Ltd. All rights reserved
Kir4.1 channels regulate swelling of astroglial processes in experimental spinal cord edema
No full textIn glial cells, inwardly rectifying K+ channels (Kir) control extracellular [K+](o) homeostasis by uptake of K+ from the extracellular space and release of K+ into the microvasculature. Kir channels were also recently implicated in K+-associated water influx and cell swelling. We studied the time-dependent expression and functional implication of the glial Kir4.1 channel for astroglial swelling in a spinal cord edema model. In this CNS region, Kir4.1 is expressed on astrocytes from the second postnatal week on and co-localizes with aquaporin 4 (AQP4). Swelling of individual astrocytes in response to osmotic stress and to pharmacological Kir blockade were analyzed by time-lapse-two-photon laser-scanning microscopy in situ. Application of 30% hypotonic solution induced astroglial soma swelling whereas no swelling was observed on astroglial processes or endfeet. Co-application of hypotonic solution and Ba2+, a Kir channel blocker, induced prominent swelling of astroglial processes. In Kir4.1(-/-) mice, however, somatic as well as process swelling was observed upon application of 30% hypotonic solutions. No additional effect was provoked upon co-application with Ba2+. Our experiments show that Kir channels prevent glial process swelling under osmotic stress. The underlying Kir channel subunit that controls glial process swelling is Kir4.1, whereas changes of the glial soma are not substantially related to Kir4.1
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