Histological Evidence of Protein Aggregation in Mutant SOD1 Transgenic Mice and in Amyotrophic Lateral Sclerosis Neural Tissues

Watanabe, Mitsunori; Dykes-Hoberg, Margaret; Culotta, Valeria C.; Price, Donald L.; Wong, Philip C.; Rothstein, Jeffrey D.

doi:10.1006/nbdi.2001.0443

Cited by 388 publications

(302 citation statements)

References 28 publications

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“…In ALS, alpha-synuclein and ubiquitin accumulate in affected neurons (9,(28)(29)(30). Lithium treatment reduces the accumulation of alphasynuclein in both MN of lamina IX (SI Fig.…”

Section: Lithium Treatment Rescues Spinal Cord Mitochondria and Facilmentioning

confidence: 99%

Lithium delays progression of amyotrophic lateral sclerosis

Fornai

Longone

Cafaro

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

504

458

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ALS is a devastating neurodegenerative disorder with no effective treatment. In the present study, we found that daily doses of lithium, leading to plasma levels ranging from 0.4 to 0.8 mEq/liter, delay disease progression in human patients affected by ALS. None of the patients treated with lithium died during the 15 months of the follow-up, and disease progression was markedly attenuated when compared with age-, disease duration-, and sex-matched control patients treated with riluzole for the same amount of time. In a parallel study on a genetic ALS animal model, the G93A mouse, we found a marked neuroprotection by lithium, which delayed disease onset and duration and augmented the life span. These effects were concomitant with activation of autophagy and an increase in the number of the mitochondria in motor neurons and suppressed reactive astrogliosis. Again, lithium reduced the slow necrosis characterized by mitochondrial vacuolization and increased the number of neurons counted in lamina VII that were severely affected in saline-treated G93A mice. After lithium administration in G93A mice, the number of these neurons was higher even when compared with saline-treated WT. All these mechanisms may contribute to the effects of lithium, and these results offer a promising perspective for the treatment of human patients affected by ALS

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“…In ALS, alpha-synuclein and ubiquitin accumulate in affected neurons (9,(28)(29)(30). Lithium treatment reduces the accumulation of alphasynuclein in both MN of lamina IX (SI Fig.…”

Section: Lithium Treatment Rescues Spinal Cord Mitochondria and Facilmentioning

confidence: 99%

Lithium delays progression of amyotrophic lateral sclerosis

Fornai

Longone

Cafaro

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

504

458

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“…One hundred and sixty-five unique fALS-linked SOD1 mutations have been identified so far, which are scattered throughout SOD1 amino acid sequence (ALSod, the Amyotrophic Lateral Sclerosis Online Genetic Database, 2012, http://alsod.iop.kcl.ac.uk/). The pathogenic role of SOD1 in ALS has been linked to the formation of protein aggregates rich in SOD1, observed both in the spinal cords of patients with ALS [17][18][19] and of transgenic mice expressing human forms of the protein [20][21][22][23] , with accumulation primarily in the late stages of the disease. The precursors of these protein aggregates are believed to be soluble oligomeric intermediates of the SOD1 aggregation process.…”

mentioning

confidence: 99%

In-cell NMR reveals potential precursor of toxic species from SOD1 fALS mutants

et al. 2014

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Mutations in the superoxide dismutase 1 (SOD1) gene are related to familial cases of amyotrophic lateral sclerosis (fALS). Here we exploit in-cell NMR to characterize the protein folding and maturation of a series of fALS-linked SOD1 mutants in human cells and to obtain insight into their behaviour in the cellular context, at the molecular level. The effect of various mutations on SOD1 maturation are investigated by changing the availability of metal ions in the cells, and by coexpressing the copper chaperone for SOD1, hCCS. We observe for most of the mutants the occurrence of an unstructured SOD1 species, unable to bind zinc. This species may be a common precursor of potentially toxic oligomeric species, that are associated with fALS. Coexpression of hCCS in the presence of copper restores the correct maturation of the SOD1 mutants and prevents the formation of the unstructured species, confirming that hCCS also acts as a molecular chaperone.

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“…Studies have focused on the role of neurotoxicity of sterol glucosides found in the seeds of Cycas circinalis that are part of the diet in Guam (2) and on the neurotoxin ␤-methylamino-alanine found in cyanobacteria (3). The spinal cords of ALS patients are characterized by pathological accumulation of sphingomyelin, ceramides, and cholesterol esters (4), which are thought to sensitize motor neurons to programmed cell death and cytoplasmic accumulation of aggregates of ubiquitin and transactivation response DNA-binding protein (TDP-43) (5,6).…”

mentioning

confidence: 99%

Liver X receptor β (LXRβ): A link between β-sitosterol and amyotrophic lateral sclerosis–Parkinson's dementia

Kim¹,

Fan²,

Gabbi³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

129

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Administration of ␤-sitosterol (42 mg/kg per day) for 3 weeks to 8-month-old male LXR␤ ؊/؊ mice resulted in the death of motor neurons in the lumbar region of the spinal cord and loss of tyrosine hydroxylase-positive dopaminergic neurons in the substantia nigra. In mice at 5 months of age, ␤-sitosterol had no observed toxicity but at 16 months of age, it caused severe paralysis and symptoms typical of dopaminergic dysfunction in LXR␤ ؊/؊ mice. WT mice were not affected by these doses of ␤-sitosterol. In 5-month-old mice, levels of the intestinal transporters, ABCG5/8 and Niemann-Pick C1 Like 1, were not affected by loss of liver X receptor (LXR) ␤ and/or treatment with ␤-sitosterol nor were there changes in plasma levels of cholesterol or ␤-sitosterol. In 8-monthold LXR␤ ؊/؊ mice there was activation of microglia in the substantia nigra pars reticulata and aggregates of ubiquitin and TDP-43 in the cytoplasm of large motor neurons in the lumbar spinal cord. Brain cholesterol concentrations were higher in LXR␤ ؊/؊ than in their WT counterparts, and treatment with ␤-sitosterol reduced brain cholesterol in both WT and LXR␤ ؊/؊ mice. In LXR␤ ؊/؊ mice but not in WT mice levels of 24-hydrocholesterol were increased upon ␤-sitosterol treatment. These data indicate that multiple mechanisms are involved in the sensitivity of LXR␤ ؊/؊ mice to ␤-sitosterol. These include activation of microglia, accumulation of protein aggregates in the cytoplasm of large motor neurons, and depletion of brain cholesterol.central nervous system ͉ cholesterol ͉ microglia ͉ neurodegenerative disease ͉ nuclear receptor

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Histological Evidence of Protein Aggregation in Mutant SOD1 Transgenic Mice and in Amyotrophic Lateral Sclerosis Neural Tissues

Cited by 388 publications

References 28 publications

Lithium delays progression of amyotrophic lateral sclerosis

Lithium delays progression of amyotrophic lateral sclerosis

In-cell NMR reveals potential precursor of toxic species from SOD1 fALS mutants

Liver X receptor β (LXRβ): A link between β-sitosterol and amyotrophic lateral sclerosis–Parkinson's dementia

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