Inhibition of the Activity of a Neuronal κB‐Binding Factor by Glutamate

doi:10.1046/j.1471-4159.1999.01851.x

Cited by 21 publications

(2 citation statements)

References 54 publications

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“…Lentivirus was added (1-10 × 10 3 pfu) after 1-2 days (DIV) and metabolites were extracted or assays were performed at 6-7 DIV. Cell death was quantified by assaying mitochondrial function (MTT assay), as previously described [32].…”

Section: Drg Culturementioning

confidence: 99%

Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients

Bloom

Mao

Strickland

et al. 2022

Mol Neurodegeneration

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Background In response to injury, neurons activate a program of organized axon self-destruction initiated by the NAD+ hydrolase, SARM1. In healthy neurons SARM1 is autoinhibited, but single amino acid changes can abolish autoinhibition leading to constitutively active SARM1 enzymes that promote degeneration when expressed in cultured neurons. Methods To investigate whether naturally occurring human variants might disrupt SARM1 autoinhibition and potentially contribute to risk for neurodegenerative disease, we assayed the enzymatic activity of all 42 rare SARM1 alleles identified among 8507 amyotrophic lateral sclerosis (ALS) patients and 9671 controls. We then intrathecally injected mice with virus expressing SARM1 constructs to test the capacity of an ALS-associated constitutively active SARM1 variant to promote neurodegeneration in vivo. Results Twelve out of 42 SARM1 missense variants or small in-frame deletions assayed exhibit constitutive NADase activity, including more than half of those that are unique to the ALS patients or that occur in multiple patients. There is a > 5-fold enrichment of constitutively active variants among patients compared to controls. Expression of constitutively active ALS-associated SARM1 alleles in cultured dorsal root ganglion (DRG) neurons is pro-degenerative and cytotoxic. Intrathecal injection of an AAV expressing the common SARM1 reference allele is innocuous to mice, but a construct harboring SARM1V184G, the constitutively active variant found most frequently among the ALS patients, causes axon loss, motor dysfunction, and sustained neuroinflammation. Conclusions These results implicate rare hypermorphic SARM1 alleles as candidate genetic risk factors for ALS and other neurodegenerative conditions.

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Section: Drg Culturementioning

confidence: 99%

Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients

Bloom

Mao

Strickland

et al. 2022

Mol Neurodegeneration

View full text Add to dashboard Cite

show abstract

“…Lentivirus was added (1– 10 × 10 3 pfu) after 1–2 days (DIV) and metabolites were extracted or assays were performed at 6–7 DIV. Cell death was quantified by assaying mitochondrial function (MTT assay), as previously described 37 .…”

Section: Methodsmentioning

confidence: 99%

Constitutively activeSARM1variants found in ALS patients induce neuropathy

Mao

Strickland

et al. 2021

Preprint

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In response to injury, neurons activate a program of organized axon self-destruction initiated by the NAD+ hydrolase SARM1. In healthy neurons SARM1 is autoinhibited, but single amino acid changes can abolish autoinhibition leading to constitutively-active SARM1 enzymes that promote degeneration when expressed in cultured neurons. To investigate whether naturally-occurring human variants might similarly disrupt SARM1 autoinhibition and potentially contribute to risk for neurodegenerative disease, we assayed the enzymatic activity of 29 rare SARM1 alleles identified among 8,507 amyotrophic lateral sclerosis (ALS) patients. Ten missense variants or small in-frame deletions exhibit constitutive NADase activity, including more than half of those that are unique to the ALS patients or that occur in multiple patients. Expression of these constitutively active ALS-associated SARM1 alleles in cultured dorsal root ganglion (DRG) neurons is pro-degenerative and cytotoxic. Intrathecal injection of an AAV expressing the common SARM1 reference allele is innocuous to mice, but a construct harboring SARM1V184G, the constitutively active variant found most frequently in the ALS patients, causes axon loss, motor dysfunction, and sustained neuroinflammation. These results implicate rare hypermorphic SARM1 alleles as candidate genetic risk factors for ALS and other neurodegenerative conditions.

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Calbindin‐D_28Kis increased in the ventral horn of spinal cord by neuroprotective factors for motor neurons

Spruill

Kuncl

2015

J of Neuroscience Research

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Slow glutamate-mediated neuronal degeneration is implicated in the pathophysiology of motor neuron diseases such as amyotrophic lateral sclerosis (ALS). The calcium-binding proteins calbindin-D28K and parvalbumin have been reported to protect neurons against excitotoxic insults. Expression of calbindin-D28K is low in adult human motor neurons, and vulnerable motor neurons additionally may lack parvalbumin. Thus, it has been speculated that the lack of calcium-binding proteins may, in part, be responsible for early degeneration of the population of motor neurons most vulnerable in ALS. Using a rat organotypic spinal cord slice system, we examined whether the most potent neuroprotective factors for motor neurons can increase the expression of calbindin-D28K or parvalbumin proteins in the postnatal spinal cord. After 4 weeks of incubation of spinal cord slices with 1) glial cell line-derived neurotrophic factor (GDNF), 2) neurturin, 3) insulin-like growth factor I (IGF-I), or 4) pigment epithelium-derived factor (PEDF), the number of calbindin-D28K -immunopositive large neurons (>20 μm) in the ventral horn was higher under the first three conditions, but not after PEDF, compared with untreated controls. Under the same conditions, parvalbumin was not upregulated by any neuroprotective factor. The same calbindin increase was true of IGF-I and GDNF in a parallel glutamate toxicity model of motor neuron degeneration. Taken together with our previous reports from the same model, which showed that all these neurotrophic factors can potently protect motor neurons from slow glutamate injury, the data here suggest that upregulation of calbindin-D28K by some of these factors may be one mechanism by which motor neurons can be protected from glutamate-induced, calcium-mediated excitotoxicity.

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Inhibition of the Activity of a Neuronal κB‐Binding Factor by Glutamate

Cited by 21 publications

References 54 publications

Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients

Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients

Constitutively activeSARM1variants found in ALS patients induce neuropathy

Calbindin‐D_28Kis increased in the ventral horn of spinal cord by neuroprotective factors for motor neurons

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Inhibition of the Activity of a Neuronal κB‐Binding Factor by Glutamate

Cited by 21 publications

References 54 publications

Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients

Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients

Constitutively activeSARM1variants found in ALS patients induce neuropathy

Calbindin‐D28Kis increased in the ventral horn of spinal cord by neuroprotective factors for motor neurons

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Product

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Calbindin‐D_28Kis increased in the ventral horn of spinal cord by neuroprotective factors for motor neurons