Advanced magnetic resonance imaging (MRI) techniques hold the promise to capture upper motor neuron loss and extramotor brain changes in amyotrophic lateral sclerosis (ALS) and as such deliver biomarkers relevant to diagnosis, prognosis... more
Advanced magnetic resonance imaging (MRI) techniques hold the promise to capture upper motor neuron loss and extramotor brain changes in amyotrophic lateral sclerosis (ALS) and as such deliver biomarkers relevant to diagnosis, prognosis and monitoring disease progression. However, a correlation between imaging parameters and clinical metrics has thus far been inconsistent across studies. We discuss the contributing factors to this clinical-imaging correlation gap as well as its implications for future research.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Although the etiology remains unclear, disturbances in calcium homoeostasis and protein folding are... more
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Although the etiology remains unclear, disturbances in calcium homoeostasis and protein folding are essential features of neurodegeneration in this disorder. Here, we review recent research findings on the interaction between endoplasmic reticulum (ER) and mitochondria, and its effect on calcium signaling and oxidative stress. We further provide insights into studies, providing evidence that structures of the ER mitochondria calcium cycle serve as a promising targets for therapeutic approaches for treatment of ALS.
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Research Interests: Physiology, Calcium, Motor neuron, Amyotrophic Lateral Sclerosis, Free Radical, and 14 moreHumans, Animals, Spinal Cord, Cell Death, Endoplasmic Reticulum, Calcium Signaling, Medical Physiology, Inclusion Bodies, Degeneration, Neurodegenerative Disease, Biochemistry and cell biology, Riluzole, Neuroprotective Agents, and Glutamate Receptor
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The endoplasmic reticulum (ER) is a multifunctional organelle involved in protein synthesis, processing and folding, in intracellular transport and calcium signalling. ER stress can be triggered by depletion of ER calcium content and the... more
The endoplasmic reticulum (ER) is a multifunctional organelle involved in protein synthesis, processing and folding, in intracellular transport and calcium signalling. ER stress can be triggered by depletion of ER calcium content and the accumulation of un- and mis-folded proteins, and relays stress signals to the ER mitochondria calcium cycle (ERMCC) and to the nucleus and protein translation machinery. The ensuing unfolded protein response (UPR) helps to cope with ER stress. Total protein synthesis is inhibited to keep protein load low, while the synthesis of ER chaperones, which assist protein folding, is induced. If cell integrity cannot be restored, signal cascades mediating cell death are activated. This review focuses on the role of ER stress and the UPR in the pathology of amyotrophic lateral sclerosis (ALS). The triggers for ER stress are as yet unclear, but induction of UPR sensor proteins, up-regulation of chaperones and induction of cell death proteins have been described in human post mortem ALS tissue and in mutant superoxide dismutase-1 (SOD1) expressing models of ALS. TDP-43 and VAPB seem to be involved in UPR signalling as well. Recent reports raise hope that UPR sensor proteins become effective therapeutic targets in the treatment of ALS.
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Amyotrophic lateral sclerosis is a multisystemic neurodegenerative disease in which degenerative processes are not exclusively restricted to the upper and lower motor neurons. Herein, imaging and neuropathological evidence for involvement... more
Amyotrophic lateral sclerosis is a multisystemic neurodegenerative disease in which degenerative processes are not exclusively restricted to the upper and lower motor neurons. Herein, imaging and neuropathological evidence for involvement of the cerebellum, which to date is not thought to be involved in ALS, is reviewed. Evidence for involvement of the cerebellum in ALS comes from several neuropathological studies. Especially ubiquitinated forms of TDP-43 and ubiquitinated p62-positive inclusions were frequently observed. The widely used transgenic SOD1-G93A ALS mice model showed prominent cerebellar immunostaining of pERK and alterations of tau expression. Studies using advanced MRI techniques demonstrated that several cerebral areas, including the cerebellum, were recruited in order to compensate for functional motor decline. Functional MRI, voxel based morphometry, and diffusion-tensor imaging showed these cerebellar alterations as being of functional and structural nature.