Biomedical subjects

L Siklos

Publications and source records attributed to L Siklos.

5 recordsLinked to original sources

PubMed2001

Calcium: the Darth Vader of ALS.

Motor neuron dysfunction and loss in amyotrophic lateral sclerosis (ALS) have been attributed to several different mechanisms, including increased intracellular calcium, glutamate excitotoxicity, oxidative stress and free radical damage, mitochondrial dysfunction, and neurofilament aggregation and dysfunction of transport mechanisms. These alterations are not mutually exclusive, and increased calcium could be a common denominator. Furthermore, the selective vulnerability of spinal motor neurons and the relative sparing of eye motor neurons represent striking features of both sporadic and familial ALS. Here we review the evidence that calcium homeostasis is altered in ALS, and that low levels of the calcium binding proteins parvalbumin and calbindin-D28K contribute to selective vulnerability by decreasing the ability of motor neurons to handle an increased calcium load, with cell injury and death as the consequence.

Amyotrophic Lateral Sclerosis↗

PubMed1997

Altered calcium homeostasis and ultrastructure in motoneurons of mice caused by passively transferred anti-motoneuronal IgG.

Calcium homeostasis and ultrastructure are altered in motor axon terminals (AT) of amyotrophic lateral sclerosis (ALS) patients and in mice injected with ALS IgG and exhibit increased density of synaptic vesicles and increased intracellular calcium. To develop an immune-mediated passive transfer experimental model of both systemic weakness and altered morphology, mice were inoculated intraperitoneally with anti-motoneuronal IgG. Animals initially manifested muscle stiffness and evidence of autonomic cholinergic hyperactivity. Electron microscopic cytochemistry within 12 hours (h) demonstrated significantly increased density of synaptic vesicles and calcium both in axon terminals of neuromuscular junctions and synaptic boutons on spinal motoneurons. After 24 h the mice were severely weak and premorbid. The number of synaptic vesicles was still larger than normal, but calcium was depleted from axon terminals and synaptic boutons. The motoneuron perikarya demonstrated the dilatation of the Golgi system and the rough endoplasmic reticulum with an increased amount of calcium. The NMDA receptor antagonist, MK-801, and the L-type calcium channel antagonist, Diltiazem, prevented clinical symptoms and some morphological alterations. These data demonstrate that high titer anti-motoneuronal IgG can induce severe weakness and produce similar ultrastructural features of motor axon terminals in human ALS and in mice injected with ALS IgG, and support a key role for calcium in selective vulnerability of motoneurons.

Amyotrophic Lateral Sclerosis↗

PubMed1996

Serum prevents glutamate-induced mitochondrial calcium accumulation in primary neuronal cultures.

The effect of serum proteins on glutamate-induced mitochondrial calcium accumulation was studied in primary cortical and hippocampal cultures using oxalate-pyroantimonate staining with electron microscopy. Cultures were prepared from rat embryos on gestational day 17-19 and cultivated for 8 days in minimal essential medium (MEM) containing 5% native horse serum. At this time cultures were exposed for 5 min to 100 micro M or 1.0 mM glutamate, followed by recovery in either serum-free or serum-containing culture medium. Mitochondrial calcium accumulation was assessed before glutamate treatment, at the end of glutamate exposure, and after 5 min, 30 min, 6 h and 24 h of recovery. Under control conditions and at the end of glutamate exposure, mitochondria contained only a few calcium deposits. If cultures were placed in serum-free medium after glutamate treatment, mitochondria were progressively loaded with calcium. At 5 min after glutamate exposure mitochondrial calcium deposits were prominent in both cortical and hippocampal cultures, followed by a further steady increase and neuronal death within 24 h. When cultures were allowed to recover after glutamate treatment in serum-containing MEM, calcium sequestration and ultrastructural changes of mitochondria were essentially absent, and neurons survived. No differences between cortical and hippocampal cultures were observed. The data demonstrate that prevention of glutamate neurotoxicity by serum proteins is associated with prevention of post-glutamate mitochondrial calcium accumulation.

Animals↗

PubMed1996

Autoimmunity and ALS.

Significant evidence has accrued suggesting that antibodies to voltage-gated calcium channel are observed in at least some patients with sporadic ALS (SALS) and that such antibodies alter the function of these ion channels in vitro and in vivo. Further, passive transfer of these immunoglobulin-containing fractions into mice produces changes at the neuromuscular junction that are very similar to changes observed in patients with SALS. These changes reflect local alterations in intracellular Ca2+ homeostasis and, in animal models, may also evidence early changes of motoneuron injury, such as Golgi apparatus swelling and fragmentation. Although not yet documented to induce motoneuron death in vivo, SALS immunoglobulins induce Ca(2+)-dependent apoptosis in a differentiated motoneuron hybrid cell line via a mechanism that involves oxidative injury. SALS immunoglobulin-mediated apoptosis in these cells is regulated by the presence of the same calcium-binding proteins that may modulate selective motoneuron vulnerability in SALS.

Amyotrophic Lateral Sclerosis↗

PubMedDate not supplied

Increased intracellular calcium triggered by immune mechanisms in amyotrophic lateral sclerosis.

Although the causes of motor neuron degeneration and death in amyotrophic lateral sclerosis (ALS) is unknown, recent evidence suggests a prominent role for increased intracellular calcium, possibly triggered by autoimmune mechanisms. The presence in ALS patients of paraproteinemias, lymphomas, lymphoid cells in the central nervous system (CNS) and the availability of animal models of immune-mediated motor neuron disease provide circumstantial evidence for autoimmunity. Direct evidence derives from the demonstration that ALS IgGs bind to voltage-gated calcium channels in 75% of sporadic cases, but not in familial ALS cases, and that ALS IgGs increase N-type and P-type calcium currents in neuronal cells and in lipid bilayers. These same ALS IgGs are cytotoxic for a motor neuron cell line (VSC 4.1) in vitro. In addition, following passive transfer to mice in vivo, ALS IgGs produce ultrastructural and calcium changes in synaptic vesicles and mitochondria of motor axon terminals, as well as in rough endoplasmic reticulum and Golgi complex of motor neuron perikarya, but not in sensory neurons or Purkinje cells. The reason for the selective vulnerability of motor neurons is not clearly defined, but a prominent possibility is the physiological absence in motor neurons of the calcium-binding proteins calbindin-D28k and parvalbumin. These studies emphasize the central role of increased intracellular calcium in motor neuron cell death in sporadic ALS, and the role of autoimmunity in triggering such increases.

Amyotrophic Lateral Sclerosis↗