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PMID:23335331

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Citation

Schipanski, A, Lange, S, Segref, A, Gutschmidt, A, Lomas, DA, Miranda, E, Schweizer, M, Hoppe, T and Glatzel, M (2013) A Novel Interaction Between Aging and ER Overload in a Protein Conformational Dementia. Genetics 193:865-76

Abstract

Intraneuronal deposition of aggregated proteins in tauopathies, Parkinson disease, or familial encephalopathy with neuroserpin inclusion bodies (FENIB) leads to impaired protein homeostasis (proteostasis). FENIB represents a conformational dementia, caused by intraneuronal polymerization of mutant variants of the serine protease inhibitor neuroserpin. In contrast to the aggregation process, the kinetic relationship between neuronal proteostasis and aggregation are poorly understood. To address aggregate formation dynamics, we studied FENIB in Caenorhabditis elegans and mice. Point mutations causing FENIB also result in aggregation of the neuroserpin homolog SRP-2 most likely within the ER lumen in worms, recapitulating morphological and biochemical features of the human disease. Intriguingly, we identified conserved protein quality control pathways to modulate protein aggregation both in worms and mice. Specifically, downregulation of the unfolded protein response (UPR) pathways in the worm favors mutant SRP-2 accumulation, while mice overexpressing a polymerizing mutant of neuroserpin undergo transient induction of the UPR in young but not in aged mice. Thus, we find that perturbations of proteostasis through impairment of the heat shock response or altered UPR signaling enhance neuroserpin accumulation in vivo. Moreover, accumulation of neuroserpin polymers in mice is associated with an age-related induction of the UPR suggesting a novel interaction between aging and ER overload. These data suggest that targets aimed at increasing UPR capacity in neurons are valuable tools for therapeutic intervention.

Links

PubMed PMC3584003 Online version:10.1534/genetics.112.149088

Keywords


Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:E5QCG0

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00274962

P

Seeded From UniProt

complete

CAEEL:E5QCG0

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00002004

P

Seeded From UniProt

complete

CAEEL:G5EFT5

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00248994

P

Seeded From UniProt

complete

CAEEL:G5EFT5

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00003970

P

Seeded From UniProt

complete

CAEEL:G5EFT5

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00002147

P

Seeded From UniProt

complete

CAEEL:E2AKA

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00091574

P

Seeded From UniProt

complete

CAEEL:E2AKA

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00002004

P

Seeded From UniProt

complete

CAEEL:Q20435

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00091838

P

Seeded From UniProt

complete

CAEEL:IRE1

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00274962

P

Seeded From UniProt

complete

CAEEL:IRE1

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00002004

P

Seeded From UniProt

complete

CAEEL:E2AK3

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00091574

P

Seeded From UniProt

complete

CAEEL:E2AK3

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00002004

P

Seeded From UniProt

complete


See also

References

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