Specific aggregation of partially folded polypeptide chains: The molecular basis of inclusion body composition

Speed, Margaret A.; Wang, Daniel I. C.; King, Jonathan

doi:10.1038/nbt1096-1283

Cited by 299 publications

(188 citation statements)

References 37 publications

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“…It has been suggested that neurotoxicity of mutant SOD arises from its possible coaggregation with and possible depletion of unidentified essential cellular components (6), although evidence in support of this hypothesis is lacking. Moreover, this model is inconsistent with biochemical studies indicating that protein aggregation occurs by specific interactions between folding intermediates and not by nonselective trapping (14). Moreover, formation of SOD inclusion bodies cannot contribute significantly to early FALS pathogenesis, because the appearance of detectable inclusion bodies in SOD1 transgenic mice is a late event-coinciding with the onset of overt motor neuron disease and the nearly synchronous loss of motor neurons (13,15).…”

contrasting

confidence: 45%

Formation of high molecular weight complexes of mutant Cu,Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis

Johnston

Dalton

Gurney³

et al. 2000

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

546

438

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Deposition of aggregated protein into neurofilament-rich cytoplasmic inclusion bodies is a common cytopathological feature of neurodegenerative disease. How-or indeed whether-protein aggregation and inclusion body formation cause neurotoxicity are presently unknown. Here, we show that the capacity of superoxide dismutase (SOD) to aggregate into biochemically distinct, high molecular weight, insoluble protein complexes (IPCs) is a gain of function associated with mutations linked to autosomal dominant familial amyotrophic lateral sclerosis. SOD IPCs are detectable in spinal cord extracts from transgenic mice expressing mutant SOD several months before inclusion bodies and motor neuron pathology are apparent. Sequestration of mutant SOD into cytoplasmic inclusion bodies resembling aggresomes requires retrograde transport on microtubules. These data indicate that aggregation and inclusion body formation are mechanistically and temporally distinct processes.F amilial amyotrophic lateral sclerosis (FALS), a dominantly inherited form of ALS, is a progressive paralytic disorder resulting from the degeneration of motor neurons in the cortex, brainstem, and spinal cord (1, 2). Between 10% and 20% of FALS cases are because of missense mutations in the SOD1 gene, which encodes the cytoplasmic metalloenzyme Cu, Znsuperoxide dismutase (SOD) (3). Mice expressing human FALS-linked SOD1 transgenes develop an age-dependent ALSlike disorder characterized by profound degeneration of spinal motor neurons and by the presence in surviving motor neurons of neurofilament-rich cytoplasmic inclusions resembling pathological inclusion bodies in spinal motor neurons in human ALS and FALS. The highly penetrant dominant inheritance pattern of both the human and mouse diseases (4), together with the absence of motor neuron disease from ''knockout'' mice lacking endogenous murine SOD1 (5), strongly suggests that FALS pathology is because of a toxic gain-of-function in SOD. The biochemical nature of this toxic gain of function, however, and the mechanism by which SOD mutations cause the degeneration of motor neurons have remained elusive, largely because of the failure to identify novel properties of mutant SOD that are unambiguously linked to early cytopathological changes.One hypothesis argues that toxicity results from the tendency of mutant SOD to ''aggregate'' into cytoplasmic inclusion bodies (6) that are evident in motor neurons from SOD transgenic mice (7,8) and in cultured COS cells (9) or motor neurons (10) expressing mutant SOD cDNA. Cytoplasmic inclusion bodies are a hallmark of motor neuron degeneration in ALS and, indeed, of nearly all neurodegenerative diseases (11). SOD is itself a component of inclusion bodies in degenerating spinal cords from FALS patients (12, 13) and in end-stage mice expressing human FALS-linked SOD1 transgenes (6,7,12). How these inclusion bodies could cause neuronal degeneration-and indeed whether the inclusions are cytotoxic or even, perhaps, cytoprotective-is controversial. It has been suggested that ne...

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contrasting

confidence: 45%

Formation of high molecular weight complexes of mutant Cu,Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis

Johnston

Dalton

Gurney³

et al. 2000

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

546

438

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“…This concept has been challenged by in vitro studies showing that protein aggregation in a cell-free system occurs by specific interactions between folding intermediates (40,41). Here, we demonstrate that spe- cific intermolecular interactions are responsible for protein aggregation within cells.…”

Section: Discussionmentioning

confidence: 84%

Aggregation of Misfolded Proteins Can Be a Selective Process Dependent upon Peptide Composition

Milewski

Mickle

Forrest

et al. 2002

Journal of Biological Chemistry

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Intracellular aggregation of misfolded proteins is observed in a number of human diseases, in particular, neurologic disorders in which expanded tracts of polyglutamine residues play a central role. A variety of other proteins are prone to aggregation when mutated, indicating that this process is a common pathologic mechanism for inherited disorders. However, little is known about the relationship between the sequence of aggregating peptides and the specificity of intracellular accumulation. Here we demonstrate that substitution of two residues eliminates aggregation of a 111-amino acid peptide derived from the C-terminal portion of the cystic fibrosis transmembrane conductance regulator (CFTR). We also show that fusion to a reporter protein considerably alters the subcellular distribution of aggregating peptide. When fused to green fluorescent protein, the peptide containing amino acids 1370 -1480 of CFTR accumulates in large perinuclear or nuclear aggregates. The same CFTR fragment devoid of green fluorescent protein localizes predominantly to discrete accumulations associated with mitochondria. Importantly, both types of accumulation are dependent on the presence of the same two amino acids within the CFTR sequence. Co-expression studies show that both CFTR-derived proteins can co-localize in large cytoplasmic/nuclear aggregates. However, neither CFTR construct accumulates in intracellular inclusions formed by N-terminal fragment of huntingtin. In addition to unique accumulation patterns, each aggregating peptide shows differences in association with chaperone proteins. Thus, our results indicate that the process of intracellular aggregation can be a selective process determined by the composition of the aggregating peptides.

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“…Amyloid formation requires self-complementary stretches found in most proteins [50], and protein homology has been considered critical for the in vitro formation of IB-like aggregates [51]. Since the co-production of different unrelated but aggregation-prone proteins leads to the formation of separate instead hybrid IBs [52], the specificity in the IB formation process was then verified.…”

Section: Inner Ib Architecture and Functionalitymentioning

confidence: 99%

Bacterial Inclusion Bodies: Discovering Their Better Half

Rinas

García‐Fruitós

Corchero

et al. 2017

Trends in Biochemical Sciences

147

123

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Bacterial inclusion bodies are functional, non-toxic amyloids occurring in recombinant bacteria that show analogies with secretory granules of the mammalian endocrine system. The scientific interest in these mesoscale protein aggregates has been historically masked by their status as a hurdle in recombinant protein production.However, insights into their molecular organization and the progressive understanding on how the cell handles the quality of recombinant polypeptides have stimulated the interest on inclusion bodies and opened ways for their usability in diverse technological fields. The engineering and tailoring of inclusion bodies as functional protein particles for materials science and biomedicine is a good example of how formerly undesired bacterial by-products can be re-discovered as promising functional materials for a broad spectrum of applications.-2 - BACKGROUND

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Specific aggregation of partially folded polypeptide chains: The molecular basis of inclusion body composition

Cited by 299 publications

References 37 publications

Formation of high molecular weight complexes of mutant Cu,Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis

Formation of high molecular weight complexes of mutant Cu,Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis

Aggregation of Misfolded Proteins Can Be a Selective Process Dependent upon Peptide Composition

Bacterial Inclusion Bodies: Discovering Their Better Half

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