Specificity in intracellular protein aggregation and inclusion body formation

Rajan, Rahul; Illing, Michelle; Bence, Neil; Kopito, Ron R.

doi:10.1073/pnas.181479798

Cited by 213 publications

(159 citation statements)

References 33 publications

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“…Together, these results suggest that the intracellular accumulation of misfolded proteins is a selective process, and that the sequence of aggregating protein determines the composition and cellular distribution of aggregates. Indeed, this conclusion is supported by two recent reports emphasizing the specificity of formation of inclusion bodies by other aggregating proteins (42,43).…”

Section: Discussionsupporting

confidence: 67%

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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Section: Discussionsupporting

confidence: 67%

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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“…Although the colocalization of Rnq1 and newly forming Sup35 aggregates supports the seeding model, our results suggest that once seeding has occurred Rnq1 and Sup35 do not coassemble, but, rather, each protein has a much greater capacity to convert itself than to cross convert. Also, colocalization without extensive coaggregation was reported (46) for an aggregation-prone rhodopsin mutant and a construct with an expanded polyQ stretch.…”

Section: Discussionmentioning

confidence: 89%

Effects of Q/N-rich, polyQ, and non-polyQ amyloids on thede novoformation of the [PSI⁺] prion in yeast and aggregation of Sup35in vitro

Derkatch

Uptain²,

Outeiro³

et al. 2004

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

202

215

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“…aggregate when expressed in the absence of its oligomeric partners (40) (Fig. 1D), and P23H rhodopsin, a folding-defective G protein-coupled receptor (40) (data not shown).…”

Section: Resultsmentioning

confidence: 94%

Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation

Iwata

Christianson

Bucci

et al. 2005

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

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301

227

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CNS neurons are endowed with the ability to recover from cytotoxic insults associated with the accumulation of proteinaceous aggregates in mouse models of polyglutamine disease, but the cellular mechanism underlying this phenomenon is unknown. Here, we show that autophagy is essential for the elimination of aggregated forms of mutant huntingtin and ataxin-1 from the cytoplasmic but not nuclear compartments. Human orthologs of yeast autophagy genes, molecular determinants of autophagic vacuole formation, are recruited to cytoplasmic but not nuclear inclusion bodies in vitro and in vivo. These data indicate that autophagy is a critical component of the cellular clearance of toxic protein aggregates and may help to explain why protein aggregates are more toxic when directed to the nucleus.autophagy ͉ huntingtin ͉ Huntington's disease P olyglutamine (polyQ) expansion disorders, such as Huntington's disease (HD) and spinocerebellar ataxia type 1, are caused by the production of mutant proteins, huntingtin (Htt) and ataxin-1 (Atx1), respectively, that adopt cytotoxic, nonnative, oligomeric, or aggregation-prone conformations because of the presence of long homopolymeric tracts of glutamine (1). The length of polyQ tracts in normal humans is polymorphic but always below a threshold of 35-40. PolyQ repeats above this threshold are invariably associated with disease, with a strong inverse correlation between repeat length and age-of-onset of neurological disease (2). These findings, together with studies on Htt fragments expressed in cell culture (3) or polyQ peptides in vitro (4), support a model in which glutamine repeats above the threshold adopt a nonnative conformation that is highly prone to self-associate into high-molecular-weight, stable aggregates. These aggregates accumulate in nuclear or cytoplasmic inclusion bodies (IBs) that are invariably associated with end-stage neurodegenerative disease in patients and animal models (5, 6). Although IBs are probably not directly responsible for cellular toxicity (5) and may even contribute to cytoprotection (7,8), the toxicity of mutant polyQ-expanded proteins appears to depend strongly on the cellular compartment in which they accumulate (9, 10). Experimental redirection of Atx1, normally a nuclear protein, to the cytoplasm, drastically reduces toxicity and IB formation in a mouse model of spinocerebellar ataxia type 1 (11). Conversely, the addition of a nuclear localization sequence to the N-terminal polyQ-containing fragment of Htt, which normally partitions between the nucleus and cytoplasm, directs it to the nucleus and increases its toxicity (12, 13). These experiments have been interpreted to indicate that the primary target of polyQ toxicity is in the nucleus. However, it also is possible that both the nucleus and cytoplasm contain targets that are equally vulnerable to these toxic proteins, but that the cytoplasm may be better endowed to neutralize or destroy the proteotoxic agent.Although protein aggregates are highly insoluble (14), animal models using condit...

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Specificity in intracellular protein aggregation and inclusion body formation

Cited by 213 publications

References 33 publications

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

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

Effects of Q/N-rich, polyQ, and non-polyQ amyloids on thede novoformation of the [PSI⁺] prion in yeast and aggregation of Sup35in vitro

Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation

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Specificity in intracellular protein aggregation and inclusion body formation

Cited by 213 publications

References 33 publications

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

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

Effects of Q/N-rich, polyQ, and non-polyQ amyloids on thede novoformation of the [PSI+] prion in yeast and aggregation of Sup35in vitro

Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation

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Effects of Q/N-rich, polyQ, and non-polyQ amyloids on thede novoformation of the [PSI⁺] prion in yeast and aggregation of Sup35in vitro