Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Protein misfolding and aggregation unify several devastating neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. There are no effective therapeutics for these disorders and none that target the reversal of the aberrant protein misfolding and aggregation that cause disease. Here, I showcase important advances to define, engineer, and apply protein disaggregases to mitigate deleterious protein misfolding and counter neurodegeneration. I focus on two exogenous protein disaggregases, Hsp104 from yeast and gene 3 protein from bacteriophages, as well as endogenous human protein disaggregases, including: (a) Hsp110, Hsp70, Hsp40, and small heat-shock proteins; (b) HtrA1; and (c) NMNAT2 and Hsp90. I suggest that protein-disaggregase modalities can be channeled to treat numerous fatal and presently incurable neurodegenerative diseases.
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PMID:Designer protein disaggregases to counter neurodegenerative disease. 2820 59

Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons. Astrocytes from diverse ALS models induce motor neuron death in co-culture. Enhancing NAD⁺ availability, or increasing the expression of the NAD⁺-dependent deacylases SIRT3 and SIRT6, abrogates their neurotoxicity in cell culture models. To determine the effect of increasing NAD⁺ availability in ALS mouse models we used two strategies, ablation of a NAD⁺-consuming enzyme (CD38) and supplementation with a bioavailable NAD⁺ precursor (nicotinamide riboside, NR). Deletion of CD38 had no effect in the survival of two hSOD1-linked ALS mouse models. On the other hand, NR-supplementation delayed motor neuron degeneration, decreased markers of neuroinflammation in the spinal cord, appeared to modify muscle metabolism and modestly increased the survival of hSOD1^G93A mice. In addition, we found altered expression of enzymes involved in NAD⁺ synthesis (NAMPT and NMNAT2) and decreased SIRT6 expression in the spinal cord of ALS patients, suggesting deficits of this neuroprotective pathway in the human pathology. Our data denotes the therapeutic potential of increasing NAD⁺ levels in ALS. Moreover, the results indicate that the approach used to enhance NAD⁺ levels critically defines the biological outcome in ALS models, suggesting that boosting NAD⁺ levels with the use of bioavailable precursors would be the preferred therapeutic strategy for ALS.
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PMID:Evaluation of the NAD⁺ biosynthetic pathway in ALS patients and effect of modulating NAD⁺ levels in hSOD1-linked ALS mouse models. 3201 38

Wallerian degeneration is a widespread mechanism of programmed axon degeneration. In the three decades since the discovery of the Wallerian degeneration slow (Wld^S) mouse, research has generated extensive knowledge of the molecular mechanisms underlying Wallerian degeneration, demonstrated its involvement in non-injury disorders and found multiple ways to block it. Recent developments have included: the detection of NMNAT2 mutations that implicate Wallerian degeneration in rare human diseases; the capacity for lifelong rescue of a lethal condition related to Wallerian degeneration in mice; the discovery of 'druggable' enzymes, including SARM1 and MYCBP2 (also known as PHR1), in Wallerian pathways; and the elucidation of protein structures to drive further understanding of the underlying mechanisms and drug development. Additionally, new data have indicated the potential of these advances to alleviate a number of common disorders, including chemotherapy-induced and diabetic peripheral neuropathies, traumatic brain injury, and amyotrophic lateral sclerosis.
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PMID:Programmed axon degeneration: from mouse to mechanism to medicine. 3215 23

Axons are essential for nervous system function and axonal pathology is a common hallmark of many neurodegenerative diseases. Over a century and a half after the original description of Wallerian axon degeneration, advances over the past five years have heralded the emergence of a comprehensive, mechanistic model of an endogenous axon degenerative process that can be activated by both injury and disease. Axonal integrity is maintained by the opposing actions of the survival factors NMNAT2 and STMN2 and pro-degenerative molecules DLK and SARM1. The balance between axon survival and self-destruction is intimately tied to axonal NAD⁺ metabolism. These mechanistic insights may enable axon-protective therapies for a variety of human neurodegenerative diseases including peripheral neuropathy, traumatic brain injury and potentially ALS and Parkinson's.
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PMID:The SARM1 axon degeneration pathway: control of the NAD⁺ metabolome regulates axon survival in health and disease. 3231 48

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