Lewy-body formation is an aggresome-related process: a hypothesis

Olanow, C. Warren; Perl, Daniel P.; DeMartino, George N.; McNaught, Kevin St. P.

doi:10.1016/s1474-4422(04)00827-0

Cited by 282 publications

(258 citation statements)

References 80 publications

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“…Although normally the ubiquitin-proteasome system selectively degrades damaged and misfolded proteins, thus protecting cells from potentially toxic effects of protein aggregation, once abnormally folded proteins aggregate, they are not degraded efficiently but rather accumulate and may even impair ubiquitin-proteasome function (30,31), as we observe with Stat5b A630P . Aggresomes are considered to be a specific and active cellular response to excessive concentrations of aberrantly folded and aggregated proteins and may be similar to inclusion bodies seen in neurodegenerative diseases (41,42). Sequestration into aggresomes or inclusion bodies may be part of a protective mechanism, serving to limit but not prevent proteasome dysfunction (30,43).…”

Section: Discussionmentioning

confidence: 99%

Aberrant Folding of a Mutant Stat5b Causes Growth Hormone Insensitivity and Proteasomal Dysfunction

Chia

Subbian

Buck

et al. 2006

Journal of Biological Chemistry

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A predicted alanine to proline substitution in Stat5b that results in profound short stature, growth hormone insensitivity, and immunodeficiency represents the first natural mutation of this transcription factor in a human. To understand the mechanisms responsible for these pathophysiological abnormalities, we have studied the biochemical and biophysical properties of the mutant Stat5b molecule. In a cellular reconstitution model growth hormone robustly stimulated tyrosine phosphorylation and transcriptional activity of wild-type Stat5b while Stat5b A630P was minimally modified and did not promote reporter gene expression. Steady state levels of Stat5bWT were ϳ3-fold higher than Stat5b A630P in cell extracts prepared with nonionic detergents. Although initial rates of biosynthesis of both proteins were similar, pulse-chase experiments established that the apparent half-life of newly synthesized soluble Stat5b A630P was <15% of Stat5b WT (3.5 h versus >24 h). Stat5bA630P accumulated in cells primarily in cytoplasmic inclusion bodies. Structural analysis of the isolated SH2 domain containing the A630P mutation showed that it resembled the wild-type SH2 segment but that it exhibited reduced thermodynamic stability and slower folding kinetics, displayed an increased hydrophobic surface, and was prone to aggregation in solution. Our results are compatible with a model in which Stat5b A630P is an inactive transcription factor by virtue of its aberrant folding and diminished solubility triggered by a misfolded SH2 domain. The potential for aggregation and formation of cytoplasmic inclusions raises the possibility that Stat5b A630P could produce additional defects through inhibition of proteasome function.Sequence-specific transcription factors are modular proteins containing distinct domains that mediate their actions, including the ability to move among different subcellular compartments, to bind to DNA in chromatin in the nucleus, and to interact with transcriptional co-activators, co-repressors, and other regulatory molecules (1). The Stat 2 family consists of seven related proteins (Stats 1, 2, 3, 4, 5a, 5b, and 6) that are responsible for many of the transcriptional effects of cytokines, growth factors, and hormones (2, 3). Stat proteins are found in latent form in the cytoplasm of unstimulated cells. They are activated upon ligand binding to its receptor by a series of steps consisting of receptorinitiated tyrosine phosphorylation, dimerization, transport into the nucleus, binding to DNA response elements on target genes, and recruitment of a complex of co-activator proteins that stimulate transcription (2, 3).Growth hormone (GH) plays a central role in regulating somatic growth and intermediary metabolism in many vertebrate species, including humans (4). Upon binding to its transmembrane receptor, GH triggers the activation of the receptor-associated tyrosine-protein kinase Jak2, which in addition to recruiting a variety of other signaling molecules leads to the activation of Stats 1, 3, 5a, and 5b (4, 5). Many ...

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Section: Discussionmentioning

confidence: 99%

Aberrant Folding of a Mutant Stat5b Causes Growth Hormone Insensitivity and Proteasomal Dysfunction

Chia

Subbian

Buck

et al. 2006

Journal of Biological Chemistry

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“…The cause of DAergic neuron death in PD remains unknown, but may involve oxidative stress and mitochondrial complex I deficiency, which may account for the accumulation of modified proteins and degeneration of DAergic neurons in the brain [1]. Complex I inhibitors, such as rotenone, have been found to cause degeneration of DAergic neurons and parkinsonian motor dysfunction [2,3].…”

Section: Introductionmentioning

confidence: 99%

Valproic acid‐mediated Hsp70 induction and anti‐apoptotic neuroprotection in SH‐SY5Y cells

Pan

Xie

et al. 2005

FEBS Letters

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Valproic acid (VPA), an anticonvulsant and moodstabilizing drug, has been reported to exert neuroprotection against a variety of insults. We now show that VPA attenuates rotenone (a potent complex I inhibitor)-induced apoptosis through the induction of heat shock protein 70, which may interact with apoptotic-protease-activating factor 1. Activation of p-Akt, p-Bcl-2, as well as p-Erk1/2 by VPA may be co-contributors to the protection.

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“…30 What is also uncertain is whether a-syn-containing Lewy bodies and neurites trigger neurodegeneration or whether they reveal appropriate cellular coping mechanisms that sequester proteins into less harmful aggregates in response to an underlying pathogenic process. 31 Lewy bodies found in young neural grafts. In the 1980s-1990s, neural grafts derived from midbrain tissue obtained from aborted fetuses were transplanted into the striata of several people with PD worldwide.…”

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confidence: 99%

A deadly spread: cellular mechanisms of α-synuclein transfer

2011

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Classically, Parkinson's disease (PD) is linked to dopamine neuron death in the substantia nigra pars compacta. Intracytoplasmic protein inclusions named Lewy bodies, and corresponding Lewy neurites found in neuronal processes, are also key features of the degenerative process in the substantia nigra. The molecular mechanisms by which substantia nigra dopamine neurons die and whether the Lewy pathology is directly involved in the cell death pathway are open questions. More recently, it has become apparent that Lewy pathology gradually involves greater parts of the PD brain and is widespread in late stages. In this review, we first discuss the role of misfolded a-synuclein protein, which is the main constituent of Lewy bodies, in the pathogenesis of PD. We then describe recent evidence that a-synuclein might transfer between cells in PD brains. We discuss in detail the possible molecular mechanisms underlying the proposed propagation and the likely consequences for cells that take up a-synuclein. Finally, we focus on aspects of the pathogenic process that could be targeted with new pharmaceutical therapies or used to develop biomarkers for early PD detection. Multiple hypotheses exist to help explain dopamine neuron cell death and Lewy body formation observed in Parkinson's disease (PD). Mutations of the main proteinaceous constituent of Lewy bodies, a-synuclein (a-syn), lead to dominant, familial disease forms. [1][2][3][4][5] More recently, genome-wide association studies (GWASs) identified variants of the a-synuclein gene (SNCA) gene, encoding a-syn protein, that are coupled to increased PD susceptibility, thus clearly linking this protein to idiopathic PD. 6-8 Furthermore, overexpressed and/or misfolded a-syn is pathogenic to cells while a-syn can be secreted from cells, enter other cells, and seed small intracellular aggregates, demonstrating a connection between a-syn and pathogenic mechanisms of PD. [9][10][11][12][13][14][15][16] In parallel, a much-discussed hypothesis by Braak and colleagues 17 states that a pathogenic agent, introduced via ingestion and/or inhalation, may transfer from the entry site along known long, unmyelinated axons to basal brain areas and eventually to brain stem and cortical regions. Although a-syn is unlikely to be this initial pathogen, it might be the initial target of the unknown agent. If a-syn is misfolded because of the action of the unknown agent, it might contribute to the spreading of pathology by moving from one cell to another and triggering misfolding in the recipient cells. If so, it might explain the surprising presence of Lewy bodies in the young neural grafts of transplanted PD patients observed more than a decade after surgery. [18][19][20][21] In this review, we discuss possible mechanisms by which a-syn could spread between cells and have deadly consequences by describing the molecular evidence for a-syn cellular exit, transit to other cells, uptake by cells, intracellular aggregation, and responses to a-syn accumulation.The Relationship Between a-Syn and PD ...

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Lewy-body formation is an aggresome-related process: a hypothesis

Cited by 282 publications

References 80 publications

Aberrant Folding of a Mutant Stat5b Causes Growth Hormone Insensitivity and Proteasomal Dysfunction

Aberrant Folding of a Mutant Stat5b Causes Growth Hormone Insensitivity and Proteasomal Dysfunction

Valproic acid‐mediated Hsp70 induction and anti‐apoptotic neuroprotection in SH‐SY5Y cells

A deadly spread: cellular mechanisms of α-synuclein transfer

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