Ubiquitin-Immunoreactive Intraneuronal Inclusions in Amyotrophic Lateral Sclerosis

Leigh, P. Nigel; Whitwell, Helen; Garofalo, O.; Buller, J.; Swash, Michael; Martin, JE; Gallo, Jean‐Marc; Weller, Roy O.; Anderton, Brian H.

doi:10.1093/brain/114.2.775

Cited by 300 publications

(190 citation statements)

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“…Indeed, ubiquitin protein epitopes and aB-crystallin were found in fibrillar neuronal inclusions in the cortex of sporadic ALS patients (21,243). This article from our laboratory led to several commentary papers, all of which supported our hypothesis that aggregation and OS in ALS should be viewed as a continuum and not as separate processes (81,113,140,314).…”

Section: G93amentioning

confidence: 60%

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Butterfield

Perluigi

Reed

et al. 2012

Antioxidants & Redox Signaling

156

142

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Several studies demonstrated that oxidative damage is a characteristic feature of many neurodegenerative diseases. The accumulation of oxidatively modified proteins may disrupt cellular functions by affecting protein expression, protein turnover, cell signaling, and induction of apoptosis and necrosis, suggesting that protein oxidation could have both physiological and pathological significance. For nearly two decades, our laboratory focused particular attention on studying oxidative damage of proteins and how their chemical modifications induced by reactive oxygen species/reactive nitrogen species correlate with pathology, biochemical alterations, and clinical presentations of Alzheimer's disease. This comprehensive article outlines basic knowledge of oxidative modification of proteins and lipids, followed by the principles of redox proteomics analysis, which also involve recent advances of mass spectrometry technology, and its application to selected age-related neurodegenerative diseases. Redox proteomics results obtained in different diseases and animal models thereof may provide new insights into the main mechanisms involved in the pathogenesis and progression of oxidativestress-related neurodegenerative disorders. Redox proteomics can be considered a multifaceted approach that has the potential to provide insights into the molecular mechanisms of a disease, to find disease markers, as well as to identify potential targets for drug therapy. Considering the importance of a better understanding of the cause/effect of protein dysfunction in the pathogenesis and progression of neurodegenerative disorders, this article provides an overview of the intrinsic power of the redox proteomics approach together with the most significant results obtained by our laboratory and others during almost 10 years of research on neurodegenerative disorders since we initiated the field of redox proteomics. Antioxid. Redox Signal. 17, 1610-1655.

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Section: G93amentioning

confidence: 60%

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Butterfield

Perluigi

Reed

et al. 2012

Antioxidants & Redox Signaling

156

142

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“…Ubiquitinated aggregates are the defining feature of FTLD-U (17), and are a prominent finding in both the brain and spinal cord of ALS patients (18). Therefore we examined brains of late stage Prp-TDP43 A315T mice using ubiquitin immunohistochem-istry.…”

Section: Resultsmentioning

confidence: 99%

TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration

Wegorzewska

Bell²,

Cairns³

et al. 2009

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

624

652

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dementia ͉ motor neuron disease ͉ neurodegeneration ͉ protein aggregation F TLD is a relatively common cause of dementia among patients with onset before 65, typically manifesting with behavioral changes or language impairment due to degeneration of subpopulations of cortical neurons in the frontal, temporal and insular regions (1). By contrast, ALS presents with muscle weakness and spasticity due to degeneration of motor neurons in both layer 5 of cortex and in the spinal cord, resulting in death from respiratory failure in 3-5 years (2, 3). Interestingly, approximately 20% of patients with ALS also develop FTLD, and approximately 15% of FLTD patients also develop ALS (4, 5).The discovery that TDP-43 is present in cytoplasmic aggregates in both ALS and FTLD-U provided evidence that the two disorders may share a common underlying mechanism (6). TDP-43 is an RNA/DNA binding protein, implicated in regulation of alternative splicing of messenger RNA, RNA stability, and transcriptional control (7). The concept that TDP-43 can play a direct role in neurodegeneration was strengthened by recent reports that dominantly inherited missense mutations in TDP-43 are found in patients with familial ALS (8-12). Mutations in TDP-43 associated with ALS cluster in the C-terminal glycine-rich region, which is involved in protein-protein interactions between TDP-43 and other heterogeneous nuclear ribonuclear proteins (hnRNPs) (13). Furthermore, C-terminal fragments of TDP-43 are observed selectively in ALS and FTLD-U tissues, suggesting that proteolytic cleavage of TDP-43 leads to protein aggregation or another toxic property (6). Therefore, several putative mechanisms of TDP-43 induced neurodegeneration are currently under investigation, including toxic protein aggregation, and/or disruption of normal TDP-43 RNA/DNA binding protein function. Here we report a mouse model of TDP-43 induced neurodegeneration which recapitulates key features of ALS and FTLD-U, including ubiquitin aggregate pathology with selective vulnerability of cortical projection neurons and spinal motor neurons, but without the presence of TDP-43 aggregates. Together with recent reports of mutations in another RNA binding protein (FUS/TLS) in familial ALS (14, 15), this supports that altered RNA-binding protein function (rather than toxic aggregation of TDP-43) likely plays a central and unexpected role in ALS pathogenesis.

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“…The number of cells immunoreactive for ubiquitin, a marker of abnormal protein degradation in neurons (20), was significantly reduced in the spinal cord of MSC-treated compared with salinetreated SOD1/G93A mice at the end stage of disease (d 125 of age) (Figure 3A Figure 3D). Next, we evaluated the effect of MSCs on reactive astrocytes and microglia.…”

Section: Msc Administration Improves Histological Pathology Traitsmentioning

confidence: 99%

Intravenous Mesenchymal Stem Cells Improve Survival and Motor Function in Experimental Amyotrophic Lateral Sclerosis

Uccelli

Milanese

Principato

et al. 2012

Mol Med

141

104

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Despite some advances in the understanding of amyotrophic lateral sclerosis (ALS) pathogenesis, significant achievements in treating this disease are still lacking. Mesenchymal stromal (stem) cells (MSCs) have been shown to be effective in several models of neurological disease. To determine the effects of the intravenous injection of MSCs in an ALS mouse model during the symptomatic stage of disease, MSCs (1 × 10 6 ) were intravenously injected in mice expressing human superoxide dismutase 1 (SOD1) carrying the G93A mutation (SOD1/G93A) presenting with experimental ALS. Survival, motor abilities, histology, oxidative stress markers and [ 3 H]D-aspartate release in the spinal cord were investigated. MSC injection in SOD1/G93A mice improved survival and motor functions compared with saline-injected controls. Injected MSCs scantly home to the central nervous system and poorly engraft. We observed a reduced accumulation of ubiquitin agglomerates and of activated astrocytes and microglia in the spinal cord of MSC-treated SOD1/G93A mice, with no changes in the number of choline acetyltransferase-and glutamate transporter type 1-positive cells. MSC administration turned around the upregulation of metallothionein mRNA expression and of the activity of the antioxidant enzyme glutathione S-transferase, both associated with disease progression. Last, we observed that MSCs reverted both spontaneous and stimulus-evoked neuronal release of [ 3 H]D-aspartate, a marker of endogenous glutamate, which is upregulated in SOD1/G93A mice. These findings suggest that intravenous administration of MSCs significantly improves the clinical outcome and pathological scores of mutant SOD1/G93A mice, thus providing the rationale for their exploitation for the treatment of ALS.

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Ubiquitin-Immunoreactive Intraneuronal Inclusions in Amyotrophic Lateral Sclerosis

Cited by 300 publications

References 0 publications

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration

Intravenous Mesenchymal Stem Cells Improve Survival and Motor Function in Experimental Amyotrophic Lateral Sclerosis

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