title: A novel interaction between aging and ER overload in a protein conformational dementia.
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.
authors: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors: Angela
authors: A
authors: Schipanski
authors: Sascha
authors: S
authors: Lange
authors: Alexandra
authors: A
authors: Segref
authors: Aljona
authors: A
authors: Gutschmidt
authors: David A
authors: DA
authors: Lomas
authors: Elena
authors: E
authors: Miranda
authors: Michaela
authors: M
authors: Schweizer
authors: Thorsten
authors: T
authors: Hoppe
authors: Markus
authors: M
authors: Glatzel
mesh_terms: D000367:Age Factors; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D018869:Heat-Shock Response; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D058105:Polymerization; D011487:Protein Conformation; D017510:Protein Folding; D015843:Serpins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D056811:Unfolded Protein Response; D000097522:Neuroserpin
chemical_list: D029742:Caenorhabditis elegans Proteins; D009479:Neuropeptides; D015843:Serpins; D000097522:Neuroserpin; C485225:SRP-2 protein, C elegans