Serpin Signatures in Prion and Alzheimer’s Diseases

Zattoni, Marco; Mearelli, Marika; Vanni, Silvia; Baldeschi, Arianna Colini; Tran, Thanh Hoa; Ferracin, Chiara; Catania, Marcella; Moda, Fabio; Fede, Giuseppe Di; Giaccone, Giorgio; Tagliavini, Fabrizio; Zanusso, Gianluigi; Ironside, James W.; Ferrer, Isidre; Legname, Giuseppe

doi:10.1007/s12035-022-02817-3

Cited by 22 publications

(23 citation statements)

References 106 publications

(130 reference statements)

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“…This upregulation was later confirmed in human frontal cortex specimens from patients affected with different types of prion diseases, both at the protein and transcript levels . A SERPINA3/SerpinA3n (its functional murine orthologue) role in prion propagation was further corroborated by our recent observation of SerpinA3n-dependent prion accumulation changes in scrapie-infected cells . Therefore, these findings make SERPINA3 an attractive target for non-PrP-targeted anti-prion drug strategies …”

Section: Introductionsupporting

confidence: 59%

“…It is noteworthy that SERPINA3 overexpression appears to be correlated also with Alzheimer’s disease, ,,− multiple system atrophy, and amyotrophic lateral sclerosis pathology; therefore, our therapeutic strategy could be potentially applied to treat other prion-like neurodegenerative disorders.…”

Section: Discussionmentioning

confidence: 99%

“…12 A SERPINA3/SerpinA3n (its functional murine orthologue) role in prion propagation was further corroborated by our recent observation of SerpinA3n-dependent prion accumulation changes in scrapie-infected cells. 13 Therefore, these findings make SERPINA3 an attractive target for non-PrPtargeted anti-prion drug strategies. 14 We report here the combined use of virtual and phenotypic screening to identify anti-prion small molecules targeting SERPINA3.…”

Section: ■ Introductionmentioning

confidence: 99%

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Innovative Non-PrP-Targeted Drug Strategy Designed to Enhance Prion Clearance

et al. 2022

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Prion diseases are a group of neurodegenerative disorders characterized by the accumulation of misfolded prion protein (called PrP Sc ). Although conversion of the cellular prion protein (PrP C ) to PrP Sc is still not completely understood, most of the therapies developed until now are based on blocking this process. Here, we propose a new drug strategy aimed at clearing prions without any direct interaction with neither PrP C nor PrP Sc . Starting from the recent discovery of SERPINA3/SerpinA3n upregulation during prion diseases, we have identified a small molecule, named compound 5 (ARN1468), inhibiting the function of these serpins and effectively reducing prion load in chronically infected cells. Although the low bioavailability of this compound does not allow in vivo studies in prion-infected mice, our strategy emerges as a novel and effective approach to the treatment of prion disease.

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Section: Introductionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Innovative Non-PrP-Targeted Drug Strategy Designed to Enhance Prion Clearance

et al. 2022

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“…Overexpression of SERPINA3 in the brain of AD patients correlates with tau hyperphosphorylation and senile plaque deposition ( 42 ). Recently, Vanni et al reported that SERPINA3 expression in the brain is increased during aging and highly upregulated in patients with neurodegenerative disorders such as prion disease and Alzheimer's disease ( 43 , 44 ). Cognitive decline is one of the most important signs preceding the onset of Alzheimer's disease.…”

Section: Discussionmentioning

confidence: 99%

Urinary proteome profiles associated with cognitive decline in community elderly residents—A pilot study

et al. 2023

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Non-invasive and simple methods enabling easy identification of individuals at high risk of cognitive decline are needed as preventive measures against dementia. This pilot study aimed to explore protein biomarkers that can predict cognitive decline using urine, which can be collected non-invasively. Study subjects were selected from participants in a cohort study of middle-aged and older community-dwelling adults who underwent cognitive testing using the Mini-Mental State Examination and provided spot urine samples at two time points with an interval of approximately 5 years. Seven participants whose cognitive function declined 4 or more points from baseline (Group D) and 7 sex- and age-matched participants whose cognitive function remained within the normal range during the same period (Group M) were selected. Urinary proteomics using mass spectrometry was performed and discriminant models were created using orthogonal partial least squares-discriminant analysis (OPLS-DA). OPLS-DA yielded two models that significantly discriminated between the two groups at baseline and follow-up. Both models had ORM1, ORM2, and SERPINA3 in common. A further OPLS-DA model using baseline ORM1, ORM2, and SERPINA3 data showed similar predictive performance for data at follow-up as it did for baseline data (sensitivity: 0.85, specificity: 0.85), with the receiver operating characteristic curve analysis yielding an area under the curve of 0.878. This prospective study demonstrated the potential for using urine to identify biomarkers of cognitive decline.

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“…Apart from various strategies that target Prp C or PrP Sc , a novel non-PrP targeted drug strategy emerged as an effective approach to treat prion disease [ 298 ]. Upregulation of SerpinA3/SerpinA3n has been associated with NDDs, including prion disease [ 299 ] as a serine protease inhibitor, it retards the protease activity responsible for clearing prion protein aggregates. With this idea, a small molecule serpin inhibitor (ARN1468) has been designed which effectively reduced prion load in scrapie’s infected ScN2a RML and ScN2a 22 L cell lines.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Prion therapeutics: Lessons from the past

Shim

Sharma

2022

Prion

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Prion diseases are a group of incurable zoonotic neurodegenerative diseases (NDDs) in humans and other animals caused by the prion proteins. The abnormal folding and aggregation of the soluble cellular prion proteins (PrP C ) into scrapie isoform (PrP Sc ) in the Central nervous system (CNS) resulted in brain damage and other neurological symptoms. Different therapeutic approaches, including stalling PrP C to PrP Sc conversion, increasing PrP Sc removal, and PrP C stabilization, for which a spectrum of compounds, ranging from organic compounds to antibodies, have been explored. Additionally, a non-PrP targeted drug strategy using serpin inhibitors has been discussed. Despite numerous scaffolds being screened for anti-prion activity in vitro , only a few were effective in vivo and unfortunately, almost none of them proved effective in the clinical studies, most likely due to toxicity and lack of permeability. Recently, encouraging results from a prion-protein monoclonal antibody, PRN100, were presented in the first human trial on CJD patients, which gives a hope for better future for the discovery of other new molecules to treat prion diseases. In this comprehensive review, we have re-visited the history and discussed various classes of anti-prion agents, their structure, mode of action, and toxicity. Understanding pathogenesis would be vital for developing future treatments for prion diseases. Based on the outcomes of existing therapies, new anti-prion agents could be identified/synthesized/designed with reduced toxicity and increased bioavailability, which could probably be effective in treating prion diseases.

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Serpin Signatures in Prion and Alzheimer’s Diseases

Cited by 22 publications

References 106 publications

Innovative Non-PrP-Targeted Drug Strategy Designed to Enhance Prion Clearance

Innovative Non-PrP-Targeted Drug Strategy Designed to Enhance Prion Clearance

Urinary proteome profiles associated with cognitive decline in community elderly residents—A pilot study

Prion therapeutics: Lessons from the past

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