Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To test the hypothesis that inhibition of axonal transport is sufficient to cause motor neuron degeneration such as that observed in amyotrophic lateral sclerosis (ALS), we engineered a targeted disruption of the dynein-dynactin complex in postnatal motor neurons of transgenic mice. Dynamitin overexpression was found to disassemble dynactin, a required activator of cytoplasmic dynein, resulting in an inhibition of retrograde axonal transport. Mice overexpressing dynamitin demonstrate a late-onset progressive motor neuron degenerative disease characterized by decreased strength and endurance, motor neuron degeneration and loss, and denervation of muscle. Previous transgenic mouse models of ALS have shown abnormalities in microtubule-based axonal transport. In this report, we describe a mouse model that confirms the critical role of disrupted axonal transport in the pathogenesis of motor neuron degenerative disease.
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PMID:Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration. 1206 19

Protein inclusions are associated with a number of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Whether protein aggregates are toxic or beneficial to cells is not known. In ALS animal models, mutant SOD1 forms aggresome-like structures in motor neurons and astrocytes. To better understand the role of protein aggregation in the progression of disease etiology, we performed a screen for small molecules that disrupt aggresome formation in cultured cells. After screening 20,000 compounds, we obtained two groups of compounds that specifically prevented aggresome formation. One group consists mainly of cardiac glycosides and will be the subject of another study. The second group contains two compounds: one is a known histone deacetylase (HDAC) inhibitor, Scriptaid, and the other is a Flavin analog, DPD. Cells treated with these molecules still contained microaggregates, but these microaggregates were not transported to microtubule organizing centers (MTOCs). The defect in transport was linked to modulation of the dynein/dynactin machinery as treatment with Scriptaid or DPD reversed mSOD-induced insolubilization of the dynactin subunits P50 dynamitin and P150(glued). Our findings suggest a connection between HDAC activity and aggresome formation and also lay the groundwork for a direct test of the role of aggresome formation in ALS etiology.
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PMID:A novel action of histone deacetylase inhibitors in a protein aggresome disease model. 1504 13

Studies from several laboratories indicate that the microtubule motors kinesin and dynein respectively participate in anterograde and retrograde axonal transport of neurofilaments. Inhibition of dynein function by transfection with a construct expressing dynamitin or intracellular delivery of anti-dynein antibodies accelerates anterograde transport, which has been interpreted to indicate that the opposing action of both motors mediates the normal distribution of neurofilaments along axons. Herein, we demonstrate that, while expression of relatively low levels of exogenous dynamitin indeed accelerated anterograde neurofilament transport along axonal neurites in culture, expression of progressively increasing levels of dynamitin induced focal accumulation of neurofilaments within axonal neurites and eventually caused neurite retraction. Inhibition of kinesin inhibited anterograde transport, but did not induce similar focal accumulations. These findings are consistent with studies indicating that perturbations in dynein activity can contribute to the aberrant accumulations of neurofilaments that accompany ALS/motor neuron disease.
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PMID:Inhibition of dynein but not kinesin induces aberrant focal accumulation of neurofilaments within axonal neurites. 1764 Jun 22

Retrograde axonal transport of cellular signals driven by dynein is vital for neuronal survival. Mouse models with defects in the retrograde transport machinery, including the Loa mouse (point mutation in dynein) and the Tg(dynamitin) mouse (overexpression of dynamitin), exhibit mild neurodegenerative disease. Transport defects have also been observed in more rapidly progressive neurodegeneration, such as that observed in the SOD1(G93A) transgenic mouse model for familial amyotrophic lateral sclerosis (ALS). Here, we test the hypothesis that alterations in retrograde signaling lead to neurodegeneration. In vivo, in vitro, and live-cell imaging motility assays show misregulation of transport and inhibition of retrograde signaling in the SOD1(G93A) model. However, similar inhibition is also seen in the Loa and Tg(dynamitin) mouse models. Thus, slowing of retrograde signaling leads only to mild degeneration and cannot explain ALS etiology. To further pursue this question, we used a proteomics approach to investigate dynein-associated retrograde signaling. These data indicate a significant decrease in retrograde survival factors, including P-Trk (phospho-Trk) and P-Erk1/2, and an increase in retrograde stress factor signaling, including P-JNK (phosphorylated c-Jun N-terminal kinase), caspase-8, and p75(NTR) cleavage fragment in the SOD1(G93A) model; similar changes are not seen in the Loa mouse. Cocultures of motor neurons and glia expressing mutant SOD1 (mSOD1) in compartmentalized chambers indicate that inhibition of retrograde stress signaling is sufficient to block activation of cellular stress pathways and to rescue motor neurons from mSOD1-induced toxicity. Hence, a shift from survival-promoting to death-promoting retrograde signaling may be key to the rapid onset of neurodegeneration seen in ALS.
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PMID:A switch in retrograde signaling from survival to stress in rapid-onset neurodegeneration. 1965 41