Article Dans Une Revue Alzheimer's Research and Therapy Année : 2025

Soluble SorLA in CSF, a novel biomarker to explore disrupted trafficking of SorLA protein in Alzheimer disease

1 CNRMAJ - Centre national de référence pour les malades Alzheimer jeunes
2 UNIROUEN - Université de Rouen Normandie
3 CHU Rouen
4 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
5 CBG - Cancer and Brain Genomics
6 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
7 HUS - Hôpitaux Universitaires de Strasbourg
8 ICube - Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie
9 FMTS - Fédération de Médecine Translationnelle de Strasbourg
10 LNCA - Laboratoire de neurosciences cognitives et adaptatives
11 Laboratoire de Biochimie et de Biologie Moléculaire
12 ECSTRRA [CRESS - U1153 / UMR_A 1125] - Epidemiology and Clinical Statistics for Tumor, Respiratory, and Resuscitation | Epidémiologie Clinique, STatistique, pour la Recherche en Santé
13 Hôpital Lariboisière-Fernand-Widal [APHP]
14 CMRR Lyon - Centre Mémoire Ressources et Recherche [Lyon]
15 CRNL-BIORAN - Équipe Biomarqueurs Radiopharmaceutiques et Neurochimiques - Radiopharmaceutical and Neurochemical Biomarkers Team
16 Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL]
17 Service de Génétique [CHU Poitiers]
18 INM - Institut des Neurosciences de Montpellier
19 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
20 UM - Université de Montpellier
21 CHU Montpellier = Montpellier University Hospital
22 MMDN - Mécanismes moléculaires dans les démences neurodégénératives
23 Laboratoire de Biologie Cellulaire et Cytologie [CHU Toulouse]
24 ToNIC - Toulouse NeuroImaging Center
25 Département Neurologie [CHU Toulouse]
26 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
27 HCL - Hospices Civils de Lyon
28 Centre de Biologie et de Pathologie - Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon]
29 Département de neurologie [Lille]
30 Excellence Laboratory LabEx DISTALZ
31 LilNCog - Lille Neurosciences & Cognition - U 1172
32 INSERM - Institut National de la Santé et de la Recherche Médicale
33 BIGR (UMR_S_1134 / U1134) - Biologie Intégrée du Globule Rouge
34 Labex Gr-Ex - Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge
Romain Castelot
  • Fonction : Auteur
Matthieu Martinet
  • Fonction : Auteur

Résumé

Background The SorLA protein, encoded by the Sortilin-related receptor 1 (SORL1) gene, is a major player in Alzheimer’s disease (AD) pathophysiology. Functional studies demonstrated that SorLA deficiency results in increased production of Aβ peptide, and thus a higher risk of AD. SorLA can be subject to proteolytic shedding at the cell surface, leading to the release of the soluble ectodomain of the protein (sSorLA) in the extracellular space. Recently, we demonstrated that a large proportion (~25%) of rare SORL1 missense variants found in AD patients alter SorLA trafficking along the constitutive secretory pathway, resulting in reduced delivery of SorLA to the plasma membrane and thus a loss of function. Here, we aimed to determine if CSF levels of sSORLA in AD patients carrying SORL1 rare variants that impact or not the trafficking of the protein can be used as a novel biomarker to explore disrupted trafficking of SorLA protein in AD. Methods A total of 151 participants were categorized into 5 study groups: controls without any neurodegenerative disease (n=30), patients suffering from Fronto-Temporal Lobar Degeneration (FTLD, n=34), AD patients not carrying a SORL1 rare variant (AD SORL1 WT, n=40), AD patients carrying SORL1 trafficking-defective variants or a protein-truncating variant (PTV) (ADSORL1 TD, n=16), and AD patients carrying a SORL1 variant with no evidence of trafficking defect (AD SORL1 nTD, n=31). Thirty-three unique rare variants of SORL1 were included for this study: 3 PTVs, 13 missense variants that impact SorLA protein trafficking in in vitro cellular assays, and 17 variants with no detectable effect on SorLA protein trafficking. We measured amounts of cleaved sSorLA by western blot in CSF samples. Results We found significantly decreased levels of sSorLA in ADSORL1 TD, compared to all other groups. According to ROC curve analysis, levels of sSorLA showed good performances to distinguish ADSORL1 TD patients from other AD patients (AUC=0.89 [95%CI: 0.81-0.97]). Conclusions Our results suggest that differential levels of sSorLA in CSF could be used as a novel marker to explore disrupted trafficking of SorLA protein in Alzheimer disease. This could help solve some proportion of variants of uncertain significance in SORL1.

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hal-05060515 , version 1 (08-12-2025)

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Romain Castelot, Aline Zarea, David Wallon, Anne Rovelet-Lecrux, Catherine Schramm, et al.. Soluble SorLA in CSF, a novel biomarker to explore disrupted trafficking of SorLA protein in Alzheimer disease. Alzheimer's Research and Therapy, 2025, 17 (1), pp.100. ⟨10.1186/s13195-025-01748-0⟩. ⟨hal-05060515⟩
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