The gray aspects of white matter disease in multiple sclerosis

Steinman, Lawrence

doi:10.1073/pnas.0903377106

Cited by 18 publications

(13 citation statements)

References 21 publications

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“…These findings correlate well with the ability of overexpressed Cryab to decrease toxicity in Alexander disease model mice (Hagemann et al, 2009). However, since Cryab can inhibit cleavage of caspase 3, influence diverse signaling pathways, and stabilize the actin cytoskeleton, among other functions (Arrigo et al, 2007; Steinman, 2009), our data extends prior work in mouse models by supporting a protein misfolding mechanism in modulation of GFAP toxicity. Further, the ability of the chemical Hsp90 inhibitor 17-AAG to rescue toxicity when administered orally (Figure 7A) suggests that protein misfolding may be an effective therapeutic target in Alexander disease.…”

Section: Discussionsupporting

confidence: 77%

Protein Misfolding and Oxidative Stress Promote Glial-Mediated Neurodegeneration in an Alexander Disease Model

Wang¹,

Colodner²,

Feany³

2011

J. Neurosci.

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Although alterations in glial structure and function commonly accompany death of neurons in neurodegenerative diseases, the role glia play in modulating neuronal loss is poorly understood. We have created a model of Alexander disease in Drosophila by expressing disease-linked mutant versions of glial fibrillary acidic protein (GFAP) in fly glia. We find aggregation of mutant human GFAP into inclusions bearing the hallmarks of authentic Rosenthal fibers. We also observe significant toxicity of mutant human GFAP to glia, which is mediated by protein aggregation and oxidative stress. Both protein aggregation and oxidative stress contribute to activation of a robust autophagic response in glia. Toxicity of mutant GFAP to glial cells induces a non-cell-autonomous stress response and subsequent apoptosis in neurons, which is dependent on glial glutamate transport. Our findings thus establish a simple genetic model of Alexander disease and further identify cellular pathways critical for glial-induced neurodegeneration.

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Section: Discussionsupporting

confidence: 77%

Protein Misfolding and Oxidative Stress Promote Glial-Mediated Neurodegeneration in an Alexander Disease Model

Wang¹,

Colodner²,

Feany³

2011

J. Neurosci.

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“…A second stage involving white and gray matter degeneration occurs later in the course. Steinman 12 reported gray matter degeneration early in the disease.…”

Section: Discussionmentioning

confidence: 98%

Tumefactive multiple sclerosis: an uncommon diagnostic challenge

Kaeser

Scali

Lanzisera

et al. 2011

Journal of Chiropractic Medicine

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Tumefactive MS may mimic the clinical and magnetic resonance imaging characteristics of glioma or a cerebral abscess. The clinical presentation, pathophysiology, differential diagnosis, role of diagnostic imaging, and treatment options of MS are described. This case report illustrates that the timely diagnosis and optimal treatment of MS require recognition of its varied, sometimes atypical, and often nonspecific clinical and imaging manifestations.

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“…This is a protein which earlier was reported as an autoimmune target in MS, with elevated levels of antibodies as well as T-cell responses in MS vs non-MS patients [17], [18]. There is an increasing literature on the importance of gray matter, neuronal and axonal involvement in MS, even at very early time-points [17].…”

Section: Discussionmentioning

confidence: 98%

Gray Matter Is Targeted in First-Attack Multiple Sclerosis

et al. 2013

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The cause of multiple sclerosis (MS), its driving pathogenesis at the earliest stages, and what factors allow the first clinical attack to manifest remain unknown. Some imaging studies suggest gray rather than white matter may be involved early, and some postulate this may be predictive of developing MS. Other imaging studies are in conflict. To determine if there was objective molecular evidence of gray matter involvement in early MS we used high-resolution mass spectrometry to identify proteins in the cerebrospinal fluid (CSF) of first-attack MS patients (two independent groups) compared to established relapsing remitting (RR) MS and controls. We found that the CSF proteins in first-attack patients were differentially enriched for gray matter components (axon, neuron, synapse). Myelin components did not distinguish these groups. The results support that gray matter dysfunction is involved early in MS, and also may be integral for the initial clinical presentation.

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The gray aspects of white matter disease in multiple sclerosis

Cited by 18 publications

References 21 publications

Protein Misfolding and Oxidative Stress Promote Glial-Mediated Neurodegeneration in an Alexander Disease Model

Protein Misfolding and Oxidative Stress Promote Glial-Mediated Neurodegeneration in an Alexander Disease Model

Tumefactive multiple sclerosis: an uncommon diagnostic challenge

Gray Matter Is Targeted in First-Attack Multiple Sclerosis

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