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Dysregulation of Inositol Polyphosphate 5-Phosphatase OCRL in Alzheimer’s Disease: Implications for Autophagy Dysfunction

par Ando, Kunie ;Htut Thazin, May;Antonelli, Eugenia Maria;Kosa, Andreea-Claudia ;López Gutiérrez, Lidia ;Quintanilla Sanchez, Carolina ;Aydin, Emmanuel ;Doeraene, Emilie ;Nagaraj, Siranjeevi ;Ramos, Ana Raquel ;Coulonval, Katia ;Roger, Pierre P. ;Brion, Jean Pierre ;Leroy, Karelle
Référence International journal of molecular sciences, 26, 12, 5827
Publication Publié, 2025-06-01

Article révisé par les pairs

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Résumé :

Autophagy is impaired in Alzheimer’s disease (AD), particularly at the stage of autophagosome–lysosome fusion. Recent studies suggest that the inositol polyphosphate 5-phosphatase OCRL (Lowe oculocerebrorenal syndrome protein) is involved in this fusion process; however, its role in AD pathophysiology remains largely unclear. In this study, we investigated the localization and expression of OCRL in post-mortem AD brains and in a 5XFAD transgenic mouse model. While OCRL RNA levels were not significantly altered, OCRL protein was markedly reduced in the RIPA-soluble fraction and positively correlated with the autophagy marker Beclin1. Immunohistochemical analysis revealed OCRL immunoreactivity in neuronal cytoplasm, granulovacuolar degeneration bodies, and plaque-associated dystrophic neurites in AD brains. Furthermore, OCRL overexpression in a FRET-based tau biosensor cell model significantly reduced the tau-seeding-induced FRET signal. These findings suggest that OCRL dysregulation may contribute to autophagic deficits and the progression of tau pathology in AD.