Tryptophan 32 mediates SOD1 toxicity in a in vivo motor neuron model of ALS and is a promising target for small molecule therapeutics

DuVal, Michèle G.; Hinge, Vijaya Kumar; Snyder, Natalie; Kanyo, Richard; Bratvold, Jenna; Pokrishevsky, Edward; Cashman, Neil R.; Blinov, N. S.; Kovalenko, Andriy; Allison, W. Ted

doi:10.1016/j.nbd.2018.11.025

Cited by 33 publications

(52 citation statements)

References 81 publications

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“…Modulation of ALS mutant SOD1 aggregation by substitution of Cys 111 to Ser has also been described [70][71][72]. The mutation of Trp 32 to Ser potently inhibited the ability of misfolded WT SOD1 to propagate between cells in culture [57,68,69]. Small molecules that bind near Trp 32 can block the seeding of mutant SOD1 aggregation in cell culture models [68,69,73].…”

Section: Introductionmentioning

confidence: 96%

“…Prior studies of ALS mutant SOD1 aggregation have shown that mutation of the unique Trp residue at position 32 of SOD1 to Ser or Phe can act in cis to suppress aggregation [38,[67][68][69]. Modulation of ALS mutant SOD1 aggregation by substitution of Cys 111 to Ser has also been described [70][71][72].…”

Section: Introductionmentioning

confidence: 98%

“…The mutation of Trp 32 to Ser potently inhibited the ability of misfolded WT SOD1 to propagate between cells in culture [57,68,69]. Small molecules that bind near Trp 32 can block the seeding of mutant SOD1 aggregation in cell culture models [68,69,73]. In the present study, we used a combination of cell culture models and in vivo seeding models to examine the role of Trp 32 in modulating mutant SOD1 aggregation.…”

Section: Introductionmentioning

confidence: 99%

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Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection

et al. 2020

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Mutations in Cu/Zn superoxide dismutase 1 (SOD1) associated with familial amyotrophic lateral sclerosis cause the protein to aggregate via a prion-like process in which soluble molecules are recruited to aggregates by conformational templating. These misfolded SOD1 proteins can propagate aggregation-inducing conformations across cellular membranes. Prior studies demonstrated that mutation of a Trp (W) residue at position 32 to Ser (S) suppresses the propagation of misfolded conformations between cells, whereas other studies have shown that mutation of Trp 32 to Phe (F), or Cys 111 to Ser, can act in cis to attenuate aggregation of mutant SOD1. By expressing mutant SOD1 fused with yellow fluorescent protein (YFP), we compared the relative ability of these mutations to modulate the formation of inclusions by ALS-mutant SOD1 (G93A and G85R). Only mutation of Trp 32 to Ser persistently reduced the formation of the amorphous inclusions that form in these cells, consistent with the idea that a Ser at position 32 inhibits templated propagation of aggregation prone conformations. To further test this idea, we produced aggregated fibrils of recombinant SOD1-W32S in vitro and injected them into the spinal cords of newborn mice expressing G85R-SOD1: YFP. The injected mice developed an earlier onset paralysis with a frequency similar to mice injected with WT SOD1 fibrils, generating a strain of misfolded SOD1 that produced highly fibrillar inclusion pathology. These findings suggest that the effect of Trp 32 in modulating the propagation of misfolded SOD1 conformations may be dependent upon the "strain" of the conformer that is propagating.

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection

et al. 2020

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“…We have found that the prion-like seeding and propagation of human wild-type SOD1 misfolding requires a tryptophan-tryptophan interaction in neighboring SOD1 molecules mediated by the single tryptophan at position 32 in SOD1 (Trp32) (10)(11)(12). Also, Trp32 mediates SOD1 aggregation in cultured cells, as well as zebrafish axonopathy in vivo (13,14). Furthermore, drugs that interact with Trp32 (15,16) can block propagated SOD1 aggregation in cell cultures and its toxicity in vivo (13,14).…”

Section: Introductionmentioning

confidence: 99%

“…Also, Trp32 mediates SOD1 aggregation in cultured cells, as well as zebrafish axonopathy in vivo (13,14). Furthermore, drugs that interact with Trp32 (15,16) can block propagated SOD1 aggregation in cell cultures and its toxicity in vivo (13,14). Trp32 in SOD1 is estimated to be more solvent exposed than 90% of other tryptophans in the human structural proteome (10), an oddity consistent with pathological functionality, such as mediating intermolecular interactions between SOD1 and other molecules.…”

Section: Introductionmentioning

confidence: 99%

Tryptophan residues in TDP-43 and SOD1 mediate the cross-seeding and toxicity of SOD1

Pokrishevsky

DuVal

McAlary

et al. 2020

Preprint

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons. Neuronal superoxide dismutase-1 (SOD1) inclusion bodies are characteristic of familial ALS with SOD1 mutations, while a hallmark of sporadic ALS is inclusions containing aggregated wild-type TAR DNA-binding protein 43 (TDP-43). Co-expression of mutant or wild-type TDP-43 with SOD1 leads to misfolding of endogenous SOD1 and aggregation of SOD1 reporter protein G85R-GFP in HEK293FT cells, and promotes synergistic axonopathy in zebrafish. This pathological interaction is dependent upon natively solvent-exposed tryptophans in SOD1 (tryptophan-32) and TDP-43 RRM1 (tryptophan-172), in concert with natively sequestered TDP-43 N-terminal domain tryptophan-68. TDP-43 RRM1 intrabodies reduce wild-type SOD1 misfolding in HEK293FT cells, via blocking tryptophan-172. Tryptophan-68 becomes antibody-accessible in aggregated TDP-43 in sporadic ALS motor neurons and cell culture. 5-fluorouridine inhibits TDP-43-induced G85R-GFP SOD1 aggregation in HEK293FT cells, and ameliorates axonopathy in zebrafish, via its interaction with SOD1 tryptophan-32. Collectively, our results establish a novel and potentially druggable tryptophan-mediated mechanism whereby two principal ALS disease effector proteins might directly interact in disease.

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Small molecules targeting different cellular pathologies for the treatment of amyotrophic lateral sclerosis

Elmansy

Reidl

Rahaman

et al. 2023

Medicinal Research Reviews

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease in which the motor neuron circuitry displays progressive degeneration, affecting mostly the motor neurons in the brain and in the spinal cord. There are no effective cures, albeit three drugs, riluzole, edaravone, and AMX0035 (a combination of sodium phenylbutyrate and taurursodiol), have been approved by the Food and Drug Administration, with limited improvement in patients. There is an urgent need to build better and more effective treatment strategies for ALS. Since the disease is very heterogenous, numerous approaches have been explored, such as targeting genetic mutations, decreasing oxidative stress and excitotoxicity, enhancing mitochondrial function and protein degradation mechanisms, and inhibiting neuroinflammation. In addition, various chemical libraries or previously identified drugs have been screened for potential repurposing in the treatment of ALS. Here, we review previous drug discovery efforts targeting a variety of cellular pathologies that occur from genetic mutations that cause ALS, such as mutations in SOD1, C9orf72, FUS, and TARDP‐43 genes. These mutations result in protein aggregation, which causes neuronal degeneration. Compounds used to target cellular pathologies that stem from these mutations are discussed and comparisons among different preclinical models are presented. Because the drug discovery landscape for ALS and other motor neuron diseases is changing rapidly, we also offer recommendations for a novel, more effective, direction in ALS drug discovery that could accelerate translation of effective compounds from animals to patients.

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Tryptophan 32 mediates SOD1 toxicity in a in vivo motor neuron model of ALS and is a promising target for small molecule therapeutics

Cited by 33 publications

References 81 publications

Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection

Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection

Tryptophan residues in TDP-43 and SOD1 mediate the cross-seeding and toxicity of SOD1

Small molecules targeting different cellular pathologies for the treatment of amyotrophic lateral sclerosis

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