Affinage

PCSK1N

ProSAAS · UniProt Q9UHG2

Length
260 aa
Mass
27.4 kDa
Annotated
2026-06-10
45 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PCSK1N (proSAAS) is a granin-like neuroendocrine precursor that serves dual roles as a selective endogenous inhibitor of prohormone convertase 1/3 (PC1/3) and as a source of bioactive neuropeptides governing feeding, anxiety, and metabolism (PMID:10632593, PMID:22164236). Its inhibitory activity resides in a C-terminal decapeptide/hexapeptide that acts as a slow, reversible competitive inhibitor of PC1/3 with nanomolar Ki, depending on a critical Lys-Arg motif (P1 Arg, P2 Lys, P4 Arg) and adopting an extended polyproline II conformation, while sparing PC2, furin, and other convertases (PMID:10816562, PMID:10812060, PMID:11435430). ProSAAS itself is cleaved by furin and carboxypeptidase D in the trans-Golgi network—an event that sorts fragments into distinct vesicles—and further processed by secretory-granule convertases (including PC2) and carboxypeptidase E into little SAAS, PEN, and big LEN (PMID:11094058, PMID:11259501, PMID:25148519); PC1/3 can also clip off the inhibitory peptide in a self-inactivation reaction (PMID:10812060). In vivo, proSAAS transiently restrains neuropeptide processing during development, regulating prodynorphin maturation in fetal brain, and its expression is repressed by the transcription factor Pax6, linking it to proinsulin processing in islet cells (PMID:20367757, PMID:23056534). The liberated peptides act as neuropeptides: big LEN signals through the Gαi/o-coupled receptor GPR171 to inhibit feeding and, in the basolateral amygdala, to hyperpolarize pyramidal neurons and modulate anxiety and fear behavior (PMID:22164236, PMID:24043826, PMID:28425495). Independently of its convertase-inhibitory role, proSAAS functions as a secreted, stress-responsive anti-aggregant chaperone that blocks fibrillation of Aβ, α-synuclein, and hIAPP through distinct hydrophobic regions, and is neuroprotective in cellular and rodent models of Alzheimer's and Parkinson's disease, including blockade of transsynaptic α-synuclein spread (PMID:24102330, PMID:27457957, PMID:35527562, PMID:39115041). Cytoplasmic proSAAS can also form liquid droplet-like spheres that sequester truncated TDP-43 and confer cytoprotection against its toxicity (PMID:35549000).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2000 High

    Established proSAAS as the first endogenous, selective inhibitor of PC1/3, defining its core biochemical identity and distinguishing it from the PC2 chaperone 7B2.

    Evidence In vitro PC1 inhibition assays with IC50/Ki measurement, synthetic peptide mapping, GST pulldown, and AtT-20 overexpression reducing POMC processing

    PMID:10632593 PMID:10812060 PMID:10816562

    Open questions at the time
    • No co-crystal structure of the proSAAS peptide bound to PC1/3
    • Physiological consequence of inhibition in vivo not yet tested at this stage
  2. 2001 High

    Resolved the structural determinants of inhibition, identifying a decapeptide with Ki ~9 nM and the critical P1/P2/P4 basic residues plus a polyproline II conformation.

    Evidence Alanine-scanning mutagenesis of synthetic peptides, kinetic inhibition assays, and circular dichroism

    PMID:11435430

    Open questions at the time
    • Conformation inferred from CD, not high-resolution structure
    • Does not address how the full-length precursor presents the inhibitory motif
  3. 2000 High

    Mapped how proSAAS is itself processed in brain and pituitary into smaller peptides, showing carboxypeptidase E shapes the inhibitory intermediate pool.

    Evidence RIA, gel filtration, HPLC, and MS of wild-type and Cpe(fat/fat) mouse tissue

    PMID:11094058

    Open questions at the time
    • Functional roles of the individual peptide products not defined at this stage
  4. 2001 High

    Identified the convertases that inactivate proSAAS by removing its C-terminal inhibitory peptide, and showed its N-terminus does not stabilize PC1/3 (unlike 7B2 toward PC2).

    Evidence In vitro cleavage with recombinant PC2/furin, thermal denaturation assays, PC2-null brain RIA, and cell cotransfection

    PMID:11259501 PMID:11719503

    Open questions at the time
    • Relative in vivo contributions of furin vs PC2 across tissues not fully quantified
  5. 2002 High

    Demonstrated that initial proSAAS cleavages and inhibitor expression are regulated independently of PC1/3, using PC12 cells lacking both convertases.

    Evidence Pulse-chase, MS, RIA in AtT-20 and PC12 cells with secretagogue stimulation

    PMID:11742530

    Open questions at the time
    • Identity of the PC1/PC2-independent processing enzyme(s) not established
  6. 2008 Medium

    Showed cross-species conservation of inhibitory potency and identified two conserved hydrophobic helical segments as functionally critical regions.

    Evidence In vitro PC1/3 inhibition and cleavage assays with Xenopus/zebrafish orthologs, conservation analysis, in situ hybridization

    PMID:18948394

    Open questions at the time
    • Function of the conserved hydrophobic segments beyond inhibition not yet linked to chaperone activity at this stage
  7. 2010 High

    Defined the in vivo role of proSAAS as a developmental brake on neuropeptide processing, with knockout revealing developmental and behavioral/metabolic phenotypes.

    Evidence ProSAAS knockout mice, peptidomics, behavioral and metabolic analysis

    PMID:20367757

    Open questions at the time
    • Why adult PC1/3 activity appears normal despite developmental requirement not explained
    • Mechanism behind locomotor and body-weight phenotypes unresolved
  8. 2012 High

    Placed Pcsk1n in a transcriptional pathway, showing Pax6 represses it to permit proper PC1/3-dependent proinsulin processing.

    Evidence Luciferase reporter, ChIP, EMSA, RNAi, enzyme assays in MIN6 cells and Pax6 mutant mice with genetic rescue

    PMID:23056534

    Open questions at the time
    • Whether other transcription factors regulate Pcsk1n in neurons unknown
  9. 2011 High

    Established proSAAS-derived big LEN and PEN as functional neuropeptides regulating food intake via a postsynaptic GPCR.

    Evidence ICV antibody neutralization, patch-clamp electrophysiology, immunohistochemical colocalization with NPY

    PMID:22164236

    Open questions at the time
    • Receptor identity not yet defined in this study
    • Identity of the retrograde messenger unknown
  10. 2013 High

    Deorphanized GPR171 as the big LEN receptor signaling through Gαi/o to regulate feeding, defining the downstream signaling axis.

    Evidence Ligand binding, receptor activity assays, GPR171 gain/loss-of-function, in vivo feeding studies

    PMID:24043826

    Open questions at the time
    • Receptors for other proSAAS peptides (PEN, little SAAS) not identified
    • Structural basis of big LEN-GPR171 binding not resolved
  11. 2013 High

    Revealed a second, processing-independent function of proSAAS as an anti-aggregant chaperone against amyloidogenic proteins, with domain mapping.

    Evidence ThT fibrillation assays, co-IP from APdE9 brain, truncation mapping, lentiviral and recombinant protein neuroprotection assays

    PMID:24042052 PMID:24102330

    Open questions at the time
    • Molecular mechanism of fibrillation inhibition not structurally defined
    • Discrepant domain assignments (97-180 for Aβ; N-terminal for hIAPP) not reconciled
  12. 2014 High

    Clarified the subcellular processing route, showing furin/carboxypeptidase D cleavage in the TGN sorts proSAAS fragments into distinct secretory vesicles.

    Evidence Site-directed mutagenesis of furin sites, AtT-20 transfection, immunofluorescence colocalization, subcellular fractionation

    PMID:25148519

    Open questions at the time
    • Sorting signals directing fragments to separate vesicles not defined
  13. 2016 High

    Extended the chaperone role to α-synuclein, localizing anti-aggregation activity to conserved residues 158-180 and providing human Parkinson's tissue and dopaminergic neuron evidence.

    Evidence In vitro fibrillation, structure-function mapping, lentiviral overexpression in primary nigral cultures, recombinant protein rescue, human substantia nigra immunohistochemistry

    PMID:27457957

    Open questions at the time
    • Causal contribution of proSAAS deposition to human disease not established
  14. 2017 High

    Extended the big LEN-GPR171 axis to anxiety and fear circuits in the basolateral amygdala and provided a small-molecule antagonist.

    Evidence BLA electrophysiology, virtual screening, small-molecule pharmacology, lentiviral knockdown, in vivo behavior

    PMID:28425495

    Open questions at the time
    • Endogenous source of big LEN in the BLA not mapped
  15. 2017 Medium

    Linked proSAAS peptides to psychostimulant behavioral plasticity, showing knockouts fail to develop locomotor sensitization.

    Evidence Quantitative peptidomics and proSAAS knockout behavioral testing (sensitization, CPP)

    PMID:28881029

    Open questions at the time
    • Single lab; specific peptide(s) and receptors mediating the sensitization phenotype not identified
  16. 2020 Medium

    Identified proSAAS as a stress-responsive chaperone, with ER and oxidative stress raising cellular levels while paradoxically inhibiting its secretion.

    Evidence qPCR, western blot, secretion ELISA under pharmacological stress in Neuro2A cells

    PMID:32607937

    Open questions at the time
    • Single lab; mechanism coupling stress to secretory retention unknown
  17. 2022 High

    Provided in vivo proof that proSAAS is neuroprotective and blocks transsynaptic α-synuclein spread in rodent Parkinson's models.

    Evidence Stereotaxic lentiviral/AAV co-injection in rat/mouse, motor testing, nigral stereology, TH densitometry, immunohistochemistry

    PMID:35527562

    Open questions at the time
    • Whether protection requires secretion or extracellular chaperone activity not dissected
  18. 2022 High

    Revealed a phase-separation-based cytoprotective function, with cytoplasmic proSAAS forming droplet-like spheres that sequester truncated TDP-43.

    Evidence Live-cell fluorescence imaging, domain-mapping mutagenesis, yeast toxicity assay

    PMID:35549000

    Open questions at the time
    • Physiological relevance of cytoplasmic proSAAS spheres in mammalian neurons unestablished
  19. 2022 Medium

    Expanded the knockout phenotype to anxiety, fear, metabolic, and circadian-shifting deficits, broadening proSAAS's behavioral footprint.

    Evidence ProSAAS knockout behavioral battery, metabolic phenotyping, circadian light-pulse protocol

    PMID:35878875

    Open questions at the time
    • Single lab; which proSAAS peptides/circuits drive the circadian and metabolic phenotypes unclear
  20. 2024 Medium

    Linked synaptic, activity-dependent proSAAS regulation to amyloid clearance, showing translational upregulation during homeostatic scaling and plaque reduction in 5xFAD mice.

    Evidence Western blot, qPCR, depolarization secretion assay, stereotaxic AAV overexpression in 5xFAD CA1, immunohistochemistry

    PMID:39115041

    Open questions at the time
    • Mechanism of translational/degradation control not defined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How proSAAS's two functional faces—convertase inhibition and anti-aggregant chaperone activity—are coordinated, and the structural basis of its substrate recognition for both convertases and amyloidogenic clients, remain unresolved.
  • No high-resolution structure of proSAAS or its complexes
  • Receptors for proSAAS peptides other than big LEN not identified
  • Causal role in human neurodegenerative disease not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 4 GO:0098772 molecular function regulator activity 4 GO:0048018 receptor ligand activity 3 GO:0140313 molecular sequestering activity 1
Localization
GO:0005576 extracellular region 3 GO:0031410 cytoplasmic vesicle 2 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-112316 Neuronal System 2
Partners
APPCPEFURINGPR171PAX6PCSK1PCSK2SNCA

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 ProSAAS is a granin-like neuroendocrine peptide precursor that functions as an endogenous inhibitor of prohormone convertase 1 (PC1) with an IC50 of 590 nM, but does not inhibit PC2. When overexpressed in AtT-20 cells, proSAAS is secreted via the regulated pathway and substantially reduces processing of the endogenous prohormone POMC. In vitro PC1 inhibition assay, overexpression in AtT-20 cells, regulated secretion assay The Journal of neuroscience High 10632593
2000 The PC1 inhibitory region of proSAAS maps to an 8-12 residue region near the C terminus containing a critical Lys-Arg sequence. Synthetic peptides from this region are competitive inhibitors of PC1 with Ki values of 14-40 nM. ProSAAS selectively inhibits PC1 but not furin, PACE4, PC5A, or PC7. A GST fusion containing the inhibitory region binds the 71 kDa but not the 85 kDa form of PC1 at pH 5.5 but not pH 7.4; binding is partially Ca2+-dependent. In vitro competitive inhibition assay with synthetic peptides, GST pulldown, pH/calcium dependence experiments The Journal of biological chemistry High 10816562
2000 ProSAAS and 7B2 share structural and functional homology. The C-terminal 40-residue SAAS CT peptide contains a hexapeptide (previously identified by combinatorial library screening) that accounts for the majority of PC1 inhibitory potency, with nanomolar Ki. Recombinant PC1 can cleave the proSAAS CT peptide following the inhibitory hexapeptide, suggesting a self-inactivation mechanism. In vitro PC1 inhibition assay, sequence analysis, recombinant PC1 cleavage assay FEBS letters High 10812060
2000 ProSAAS is processed in mouse brain and pituitary into smaller peptides including little SAAS, PEN, and big LEN. Processing is slightly impaired in Cpe(fat/fat) mice, causing accumulation of partially processed peptides including a C-terminally extended form of PEN that inhibits PC1 activity. Radioimmunoassay, gel filtration, reverse-phase HPLC, mass spectrometry of brain/pituitary fractions from wild-type and Cpe(fat/fat) mice The Journal of biological chemistry High 11094058
2001 The decapeptide proSAAS-(235-244) VLGALLRVKR is the most potent reversible competitive PC1 inhibitor with Ki ~9 nM. Systematic alanine-scanning mutagenesis identified that P1 Arg, P2 Lys, P4 Arg are critical for inhibition, while P3 Val and P5/P6/P1' Leu residues significantly affect potency and selectivity. The extended peptide proSAAS-(235-246) is a competitive substrate cleaved by PC1 at KR244. Circular dichroism revealed an extended poly-L-proline II type conformation for the most potent inhibitor. In vitro PC1 inhibition assay, alanine scanning mutagenesis of synthetic peptides, circular dichroism, molecular modeling The Journal of biological chemistry High 11435430
2001 PC2 and furin can each cleave recombinant proSAAS in vitro, rapidly removing the C-terminal inhibitory peptide. In PC2-null mouse brains, the C-terminal proSAAS peptide is not processed as efficiently as in wild-type, demonstrating that PC2 is partially responsible for this cleavage in vivo. In vitro cleavage assay with recombinant PC2 and furin, RIA analysis of brain extracts from PC2 null mice Journal of neurochemistry High 11259501
2001 The N-terminal domain of proSAAS (proSAAS-1-180) does not stabilize PC1 activity or protect it from thermal denaturation in vitro, unlike the effect of 7B2 N-terminal domain on PC2. Cotransfection of proSAAS-(1-225) or proSAAS-(1-180) with PC1 in HEK293 or CHO/PC1 cells reduced PC1 activity detected in medium without reducing PC1 mass, suggesting proSAAS-mediated inactivation. In AtT-20 cells, proSAAS-(1-225) slowed processing of POMC and proenkephalin. In vitro thermal denaturation assay, cotransfection in HEK293/CHO/AtT-20 cells, pulse-chase analysis The Journal of biological chemistry High 11719503
2002 ProSAAS is processed in AtT-20 and PC12 cells into peptides including little SAAS, PEN, and big LEN via the regulated secretory pathway; secretion is stimulated by secretagogues. Because PC12 cells lack PC1 and PC2 yet efficiently cleave proSAAS, the initial cleavages do not require either enzyme. Long-term secretagogue treatment does not affect proSAAS mRNA, unlike PC1 mRNA which increases ~60-80%, indicating enzyme and inhibitor are independently regulated. Pulse-chase analysis with [3H]leucine, mass spectrometry, chromatography, RIA in AtT-20 and PC12 cells The Biochemical journal High 11742530
2004 In AtT-20 cells under pulse-chase conditions, proSAAS expression inhibits both C-terminal PC1 processing and POMC processing. In HEK293 cells, the SAAS CT peptide portion of chimeric constructs inhibits zymogen processing and decreases C-terminal PC1 processing. The PC1 propeptide expressed in trans reduces C-terminal PC1 processing and inhibits POMC processing. Pulse-chase analysis, transient transfection in AtT-20 and HEK293 cells, chimeric construct expression The Journal of endocrinology Medium 15283695
2008 Non-mammalian proSAAS homologs from Xenopus and zebrafish (29-30% overall identity to mouse proSAAS) inhibit mouse PC1/3 with nanomolar inhibition constants. Two 14-16 residue hydrophobic segments (predicted alpha-helices) and sequences containing basic convertase cleavage sites are highly conserved across vertebrates, identifying these as functionally critical regions. Both non-mammalian proSAAS proteins are cleaved in vitro by PC2 and furin. In vitro PC1/3 inhibition assay, in vitro cleavage assay, sequence conservation analysis, in situ hybridization Endocrinology Medium 18948394
2010 ProSAAS knockout mice show complete adult-like processing of prodynorphin in the prenatal brain instead of the incomplete processing seen in wild-type fetal brains where inhibitory proSAAS intermediates transiently accumulate, demonstrating that proSAAS directly regulates neuropeptide processing in vivo during embryonic development. Adult proSAAS knockout mice have normal peptide levels, suggesting PC1/3 activity is unaffected by proSAAS absence in adults. ProSAAS knockout mice exhibit decreased locomotion and male-specific 10-15% body weight decrease. Genetic knockout mouse model, peptidomics, glucose tolerance testing, behavioral analysis Journal of neurochemistry High 20367757
2011 ProSAAS-derived peptides big LEN and PEN function as neuropeptides regulating food intake: intracerebroventricular injection of antibodies to big LEN or PEN significantly reduced food intake in fasted mice. Big LEN produced rapid and reversible inhibition of synaptic glutamate release in parvocellular hypothalamic paraventricular neurons via a postsynaptic G protein-coupled receptor, releasing a retrograde synaptic messenger. Big LEN and PEN colocalize with neuropeptide Y in arcuate nucleus neurons. ICV antibody injection, whole-cell patch clamp electrophysiology, immunohistochemistry colocalization PloS one High 22164236
2012 Pax6 directly binds the Pcsk1n promoter and down-regulates proSAAS expression, as demonstrated by luciferase reporter assay, chromatin immunoprecipitation, and EMSA. Pax6 deficiency elevates proSAAS levels, which inhibits PC1/3 C-terminal cleavage and activity, thereby reducing proinsulin processing. Co-knockdown of Pax6 and Pcsk1n rescues the proinsulin processing defect caused by Pax6 knockdown alone. Luciferase reporter assay, ChIP, EMSA, RNAi knockdown, western blot, enzyme activity assay in MIN6 cells and Pax6 mutant mice PloS one High 23056534
2013 GPR171 is the receptor for the proSAAS-derived peptide BigLEN. BigLEN activates GPR171 via Gαi/o signaling in mouse hypothalamus and Neuro2A cells. The four C-terminal amino acids of BigLEN are sufficient to bind and activate GPR171. ShRNA knockdown of hypothalamic GPR171 decreases BigLEN signaling and alters food intake and metabolism. The BigLEN-GPR171 system is involved in regulation of feeding. Ligand-binding assay, receptor-activity assay, GPR171 overexpression and shRNA knockdown, in vivo feeding studies, orphan receptor screening Proceedings of the National Academy of Sciences of the United States of America High 24043826
2013 ProSAAS functions as an anti-aggregant chaperone against Aβ(1-42) fibrillation in vitro at molar ratios of 1:10. ProSAAS co-immunoprecipitates with Aβ from APdE9 mouse brain lysates. The anti-aggregation function maps to residues 97-180. ProSAAS overexpression (lentiviral) or recombinant proSAAS in medium blocks Aβ(1-42)-induced neurocytotoxicity in Neuro2A cells. In vitro fibrillation assay (ThT), co-immunoprecipitation from mouse brain, structure-function analysis with truncation constructs, lentiviral overexpression, cytotoxicity assay Journal of neurochemistry High 24102330
2013 ProSAAS and 7B2 block human islet amyloid polypeptide (hIAPP) fibrillation in vitro. Structure-function studies mapped the anti-aggregation activity to a central region within 21-kDa 7B2 and the N-terminal region of proSAAS. Both chaperones blocked cytotoxic effects of exogenous hIAPP on Rin5f cells. In vitro fibrillation assay, structure-function truncation analysis, cell cytotoxicity assay FEBS letters Medium 24042052
2014 Initial processing of proSAAS is mediated by furin (and/or furin-like enzymes) and carboxypeptidase D in the Golgi or trans-Golgi network; smaller peptide forms are generated by secretory granule prohormone convertases and carboxypeptidase E. Site-directed mutagenesis of the two furin consensus sites (P4 Arg→Lys) in proSAAS expressed in AtT-20 cells significantly increased colocalization of PEN and SAAS peptides, demonstrating that furin cleavage in the TGN sorts proSAAS fragments into distinct vesicles. Site-directed mutagenesis, AtT-20 transfection, immunofluorescence colocalization, subcellular fractionation PloS one High 25148519
2016 ProSAAS potently inhibits α-synuclein fibrillation in vitro; residues 158-180, containing a largely conserved element, are critical for this anti-aggregation activity. ProSAAS-encoding lentivirus blocks α-synuclein-induced cytotoxicity in primary cultures of nigral dopaminergic neurons, and recombinant proSAAS blocks α-synuclein cytotoxicity in SH-SY5Y cells. ProSAAS is associated with aggregated synuclein deposits in substantia nigra of Parkinson's disease patients. In vitro fibrillation assay, structure-function analysis, lentiviral overexpression in primary nigral cultures, recombinant protein cytotoxicity assay, immunohistochemistry on human tissue Proceedings of the National Academy of Sciences of the United States of America High 27457957
2017 The BigLEN-GPR171 system in the basolateral amygdala (BLA) regulates anxiety-like behavior and contextual fear conditioning. BigLEN hyperpolarizes BLA pyramidal neurons via GPR171. A small molecule GPR171 antagonist (MS0021570_1) blocks BigLEN-mediated hyperpolarization of BLA neurons and BigLEN-induced feeding; systemic or intra-BLA administration, or lentiviral knockdown of GPR171 in the BLA, reduces anxiety-like behavior and fear conditioning. Electrophysiology (BLA neuron hyperpolarization), virtual screening/homology modeling, small molecule pharmacology, lentiviral knockdown, in vivo behavioral assays Neuropsychopharmacology High 28425495
2017 ProSAAS knockout mice fail to sensitize to cocaine or amphetamine (no locomotor sensitization), while rewarding effects (conditioned place preference) remain intact. Five of ten peptides significantly decreased in nucleus accumbens and VTA of cocaine-treated mice are derived from proSAAS, indicating cocaine modulates proSAAS peptide levels in specific brain regions. Quantitative peptidomics, proSAAS knockout mouse behavioral analysis (open field locomotion, sensitization, CPP) Journal of neurochemistry Medium 28881029
2020 Cell stress (tunicamycin, thapsigargin, cobalt chloride hypoxic inducer, sodium arsenite) increases cellular proSAAS mRNA and protein in Neuro2A cells while paradoxically inhibiting proSAAS secretion, indicating that proSAAS is a stress-responsive secretory chaperone whose cellular retention is upregulated during ER and oxidative stress. qPCR, western blot, ELISA for secretion, pharmacological stress induction in Neuro2A cells Cell stress & chaperones Medium 32607937
2022 Cytoplasmic expression of proSAAS generates membraneless ~2 μm spheres with liquid droplet-like properties that selectively sequester a C-terminally truncated form of TDP-43 via its prion-like domain. Three proSAAS sequences are required for sphere formation and TDP-43 encapsulation: a predicted coiled-coil, a conserved region (residues 158-169), and a positively charged sequence (residues 181-185). Lysine substitution in residues 181-185 causes nuclear translocation of proSAAS. ProSAAS expression confers cytoprotection against full-length TDP-43 toxicity in yeast. Fluorescence live cell imaging, site-directed mutagenesis, yeast toxicity assay, domain mapping with deletion/point mutant constructs ACS chemical neuroscience High 35549000
2022 Lentiviral co-injection of proSAAS with human α-synuclein AAV into rat substantia nigra profoundly reduced motor asymmetry, protected nigral TH-positive neurons and striatal TH-positive terminals, and reduced human α-synuclein protein levels. In a vagal α-synuclein transmission model, proSAAS AAV co-injection reduced α-synuclein-positive neurites in pons and caudal midbrain, demonstrating blockade of transsynaptic α-synuclein spread. Stereotaxic lentiviral/AAV injection in rat/mouse models, motor behavioral testing, nigral stereology, TH densitometry, immunohistochemistry Journal of Parkinson's disease High 35527562
2022 ProSAAS knockout mice display anxiety-like behaviors, reduced cued fear, impaired fear-potentiated startle, reduced water consumption, elevated respiratory exchange ratio during light phase (indicating decreased fat metabolism), and inability to shift circadian clock upon light pulse despite normal circadian activity patterns. Genetic knockout mouse model, behavioral testing battery (open field, light-dark, elevated zero maze, fear conditioning, startle), metabolic phenotyping, circadian light-pulse protocol Genes, brain, and behavior Medium 35878875
2024 ProSAAS protein levels in primary hippocampal neurons are substantially upregulated during homeostatic scaling (more so than 7B2 or CPE), while proSAAS mRNA remains static, suggesting translational or degradation control. ProSAAS is released upon depolarization of differentiated hippocampal cultures, supporting synaptic localization. Stereotaxic AAV2/1-mediated overexpression of proSAAS in the CA1 region of 5xFAD mice significantly reduces amyloid plaque burden. Western blotting, qPCR, depolarization-induced secretion assay, stereotaxic AAV injection in 5xFAD mice, immunohistochemistry Journal of neurochemistry Medium 39115041

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Identification and characterization of proSAAS, a granin-like neuroendocrine peptide precursor that inhibits prohormone processing. The Journal of neuroscience : the official journal of the Society for Neuroscience 206 10632593
2000 The C-terminal region of proSAAS is a potent inhibitor of prohormone convertase 1. The Journal of biological chemistry 82 10816562
2013 GPR171 is a hypothalamic G protein-coupled receptor for BigLEN, a neuropeptide involved in feeding. Proceedings of the National Academy of Sciences of the United States of America 71 24043826
2000 The SAAS granin exhibits structural and functional homology to 7B2 and contains a highly potent hexapeptide inhibitor of PC1. FEBS letters 64 10812060
2011 ProSAAS-derived peptides are colocalized with neuropeptide Y and function as neuropeptides in the regulation of food intake. PloS one 53 22164236
2001 Inhibitory specificity and potency of proSAAS-derived peptides toward proprotein convertase 1. The Journal of biological chemistry 48 11435430
2000 ProSAAS processing in mouse brain and pituitary. The Journal of biological chemistry 47 11094058
2013 A novel function for proSAAS as an amyloid anti-aggregant in Alzheimer's disease. Journal of neurochemistry 43 24102330
2001 Tissue distribution and processing of proSAAS by proprotein convertases. Journal of neurochemistry 43 11259501
2016 The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity. Proceedings of the National Academy of Sciences of the United States of America 42 27457957
2010 The propeptide precursor proSAAS is involved in fetal neuropeptide processing and body weight regulation. Journal of neurochemistry 39 20367757
2002 Processing of proSAAS in neuroendocrine cell lines. The Biochemical journal 39 11742530
2001 Distribution of proSAAS-derived peptides in rat neuroendocrine tissues. Neuroscience 39 11672612
2001 Functional characterization of ProSAAS: similarities and differences with 7B2. The Journal of biological chemistry 39 11719503
2010 Circadian integration of glutamatergic signals by little SAAS in novel suprachiasmatic circuits. PloS one 33 20830308
2015 SAAS-CNV: A Joint Segmentation Approach on Aggregated and Allele Specific Signals for the Identification of Somatic Copy Number Alterations with Next-Generation Sequencing Data. PLoS computational biology 30 26583378
2013 Blockade of islet amyloid polypeptide fibrillation and cytotoxicity by the secretory chaperones 7B2 and proSAAS. FEBS letters 30 24042052
2001 Coexpression of proprotein convertase SPC3 and the neuroendocrine precursor proSAAS. Endocrinology 29 11517193
2017 The BigLEN-GPR171 Peptide Receptor System Within the Basolateral Amygdala Regulates Anxiety-Like Behavior and Contextual Fear Conditioning. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 26 28425495
2004 Prohormone convertase 1 (PC1) processing and sorting: effect of PC1 propeptide and proSAAS. The Journal of endocrinology 25 15283695
2003 An N-terminal fragment of ProSAAS (a granin-like neuroendocrine peptide precursor) is associated with tau inclusions in Pick's disease. Biochemical and biophysical research communications 24 12914799
2002 ProSAAS and prohormone convertase 1 are broadly expressed during mouse development. Brain research. Gene expression patterns 24 15018810
2012 Pax6 directly down-regulates Pcsk1n expression thereby regulating PC1/3 dependent proinsulin processing. PloS one 22 23056534
2008 Identification of proSAAS homologs in lower vertebrates: conservation of hydrophobic helices and convertase-inhibiting sequences. Endocrinology 19 18948394
2014 ProSAAS-derived peptides are differentially processed and sorted in mouse brain and AtT-20 cells. PloS one 18 25148519
2023 SaaS sRNA promotes Salmonella intestinal invasion via modulating MAPK inflammatory pathway. Gut microbes 17 37158502
2020 Increased expression and retention of the secretory chaperone proSAAS following cell stress. Cell stress & chaperones 13 32607937
2017 ProSAAS-derived peptides are regulated by cocaine and are required for sensitization to the locomotor effects of cocaine. Journal of neurochemistry 13 28881029
2023 Citrullinated fibrinogen-SAAs complex causes vascular metastagenesis. Nature communications 12 37620307
2022 The proSAAS Chaperone Provides Neuroprotection and Attenuates Transsynaptic α-Synuclein Spread in Rodent Models of Parkinson's Disease. Journal of Parkinson's disease 12 35527562
2023 A Small RNA, SaaS, Promotes Salmonella Pathogenicity by Regulating Invasion, Intracellular Growth, and Virulence Factors. Microbiology spectrum 11 36688642
2022 Sequestration of TDP-43216-414 Aggregates by Cytoplasmic Expression of the proSAAS Chaperone. ACS chemical neuroscience 11 35549000
2004 Analysis of cDNA sequences of feline SAAs. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 10 15185497
2022 Mice lacking proSAAS display alterations in emotion, consummatory behavior and circadian entrainment. Genes, brain, and behavior 8 35878875
2024 Using multi-omics to explore the effect of Bacillus velezensis SAAS-63 on resisting nutrient stress in lettuce. Applied microbiology and biotechnology 6 38683244
2025 PCSK1N as a Tumor Size Marker and an ER Stress Response Protein in Corticotroph Pituitary Adenomas. The Journal of clinical endocrinology and metabolism 5 39288010
2024 A trans-acting sRNA SaaS targeting hilD, cheA and csgA to inhibit biofilm formation of S. Enteritidis. Journal of advanced research 4 38852803
2024 ProSAAS is preferentially up-regulated during homeostatic scaling and reduces amyloid plaque burden in the 5xFAD mouse hippocampus. Journal of neurochemistry 2 39115041
2024 SaaS sRNA promotes the interfering effect of Salmonella on hepatic iron metabolism via modulating ferroportin 1. iScience 1 39935453
2022 ProSAAS peptide of the granin protein family in biochemical diagnostics of pheochromocytoma. Endokrynologia Polska 1 35381093
2016 Identification of single amino acid substitutions (SAAS) in neuraminidase from influenza a virus (H1N1) via mass spectrometry analysis coupled with de novo peptide sequencing. Rapid communications in mass spectrometry : RCM 1 27539435
2025 The neuronal chaperone proSAAS is highly expressed in the retina. PloS one 0 40378115
2025 ProSAAS neuropeptides and receptors GPR171 and GPR83: Potential therapeutic applications for pain, anxiety, and body weight regulation. The Journal of pharmacology and experimental therapeutics 0 40450835
2024 ProSAAS is Preferentially Secreted from Neurons During Homeostatic Scaling and Reduces Amyloid Plaque Size in the 5xFAD Mouse Hippocampus. bioRxiv : the preprint server for biology 0 38712265
2020 Publisher Correction: Increased expression and retention of the secretory chaperone proSAAS following cell stress. Cell stress & chaperones 0 32691307

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