A novel interaction between aging and ER overload in a protein conformational dementia

TY - JOUR

T1 - A novel interaction between aging and ER overload in a protein conformational dementia

AU - Schipanski, Angela

AU - Lange, Sascha

AU - Segref, Alexandra

AU - Gutschmidt, Aljona

AU - Lomas, David A

AU - Miranda, Elena

AU - Schweizer, Michaela

AU - Hoppe, Thorsten

AU - Glatzel, Markus

PY - 2013/3/1

Y1 - 2013/3/1

N2 - 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.

AB - 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.

KW - Age Factors

KW - Amino Acid Sequence

KW - Animals

KW - Caenorhabditis elegans

KW - Caenorhabditis elegans Proteins

KW - Endoplasmic Reticulum

KW - Endoplasmic Reticulum Stress

KW - Heat-Shock Response

KW - Hippocampus

KW - Humans

KW - Inclusion Bodies

KW - Mice

KW - Mice, Mutant Strains

KW - Molecular Sequence Data

KW - Neurons

KW - Neuropeptides

KW - Point Mutation

KW - Polymerization

KW - Protein Conformation

KW - Protein Folding

KW - Serpins

KW - Signal Transduction

KW - Unfolded Protein Response

U2 - 10.1534/genetics.112.149088

DO - 10.1534/genetics.112.149088

M3 - SCORING: Journal article

C2 - 23335331

VL - 193

SP - 865

EP - 876

JO - GENETICS

JF - GENETICS

SN - 0016-6731

IS - 3

ER -