Alterations of NMDAR Subunits in the Cerebrospinal Fluid Across Neurodegenerative and Immunological Disorders
Por:
Escamilla, S, Pérez-González, R, Márquez-Marco, C, Camporesi, E, Brinkmalm, G, Padovani, A, Pilotto, A, Tolassi, C, Arici, D, Volonghi, I, Zetterberg, H, Blennow, K, Pérez-Pérez, J, Kulisevsky, J, Cuchillo-Ibáñez, I, Sáez-Valero, J
Publicada:
1 ago 2025
Resumen:
N-methyl-D-aspartate receptors (NMDARs) are glutamate-binding calcium channels that play a key role in brain function and have been linked to many neurological disorders. NMDARs are multi-pass membrane heterotetrameric complexes composed of two compulsory GluN1 subunits and two GluN2 (A-D) or GluN3 (A-B) subunits, from which GluN1, GluN2B, GluN2A, and GluN3A are widely expressed in the adult brain. This study assesses the presence of GluN1, GluN2B, GluN2A, and GluN3A in the cerebrospinal fluid (CSF) from healthy individuals, viral and autoimmune encephalitis, Huntington's disease (HD) and Alzheimer's disease (AD) patients. Samples were run in SDS-PAGE under reducing conditions and resolved with different anti-ectodomain and anti-C-terminal antibodies that combined with immunoprecipitation analyses, served to demonstrate the presence of full-length GluN1, GluN2A, GluN2B, and GluN3A in CSF. These NMDAR subunit complexes are not associated with extracellular vesicles. As a proof of concept of the identity of NMDAR subunits in the CSF, we demonstrated reduced levels of GluN1 in the CSF from patients with autoimmune encephalitis caused by anti-GluN1 antibodies compared with other causes of encephalitis; and showed a depletion of CSF GluN3A in a Grin3a knockout mouse model. Moreover, we observed higher GluN3A levels in CSF in both asymptomatic and symptomatic HD patients; while GluN2A levels were lower in CSF from AD patients. In conclusion, here we demonstrate the presence of NMDAR full-length subunits in CSF and that changes in NMDAR subunits balance could serve to identify alterations related to pathological conditions.
Filiaciones:
Escamilla, S:
Univ Miguel Hernandez, Inst Neurociencias Alicante, CSIC, Sant Joan Dalacant, Alicante, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Inst Invest Sanitaria & Biomed Alicante ISABIAL Al, Alicante, Spain
Pérez-González, R:
Univ Miguel Hernandez, Inst Neurociencias Alicante, CSIC, Sant Joan Dalacant, Alicante, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Inst Invest Sanitaria & Biomed Alicante ISABIAL Al, Alicante, Spain
Márquez-Marco, C:
Univ Miguel Hernandez, Inst Neurociencias Alicante, CSIC, Sant Joan Dalacant, Alicante, Spain
Camporesi, E:
Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Dept Psychiat & Neurochem, Gothenburg, Sweden
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
Brinkmalm, G:
Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Dept Psychiat & Neurochem, Gothenburg, Sweden
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
Padovani, A:
Univ Brescia, Dept Clin & Expt Sci, Neurol Unit, Brescia, Italy
ASST Spedali Civili Hosp, Dept Continu Care & Frailty, Neurol Unit, Brescia, Italy
Univ Brescia, Neurobiorepository & Lab Adv Biol Markers, Brescia, Italy
ASST Spedali Civili Hosp, Brescia, Italy
Univ Brescia, Brain Hlth Ctr, Brescia, Italy
Pilotto, A:
Univ Brescia, Dept Clin & Expt Sci, Neurol Unit, Brescia, Italy
ASST Spedali Civili Hosp, Dept Continu Care & Frailty, Neurol Unit, Brescia, Italy
Univ Brescia, Neurobiorepository & Lab Adv Biol Markers, Brescia, Italy
ASST Spedali Civili Hosp, Brescia, Italy
Tolassi, C:
Univ Brescia, Dept Clin & Expt Sci, Neurol Unit, Brescia, Italy
ASST Spedali Civili Hosp, Dept Continu Care & Frailty, Neurol Unit, Brescia, Italy
Univ Brescia, Neurobiorepository & Lab Adv Biol Markers, Brescia, Italy
ASST Spedali Civili Hosp, Brescia, Italy
Arici, D:
Univ Brescia, Dept Clin & Expt Sci, Neurol Unit, Brescia, Italy
ASST Spedali Civili Hosp, Dept Continu Care & Frailty, Neurol Unit, Brescia, Italy
Univ Brescia, Neurobiorepository & Lab Adv Biol Markers, Brescia, Italy
ASST Spedali Civili Hosp, Brescia, Italy
Volonghi, I:
Univ Brescia, Dept Clin & Expt Sci, Neurol Unit, Brescia, Italy
ASST Spedali Civili Hosp, Dept Continu Care & Frailty, Neurol Unit, Brescia, Italy
Univ Brescia, Neurobiorepository & Lab Adv Biol Markers, Brescia, Italy
ASST Spedali Civili Hosp, Brescia, Italy
Zetterberg, H:
Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Dept Psychiat & Neurochem, Gothenburg, Sweden
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
UCL, Inst Neurol, Dept Neurodegenerat Dis, London, England
UCL, UK Dementia Res Inst, London, England
Hong Kong Ctr Neurodegenerat Dis, Hong Kong, Peoples R China
UW Dept Med, Sch Med & Publ Hlth, Madison, WI USA
Blennow, K:
Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Dept Psychiat & Neurochem, Gothenburg, Sweden
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
Sorbonne Univ, Pitie Salpetriere Hosp, Paris Brain Inst, ICM, Paris, France
Univ Sci & Technol China, Inst Aging & Brain Disorders, Neurodegenerat Disorder Res Ctr, Div Life Sci & Med, Hefei, Peoples R China
Univ Sci & Technol China, Inst Aging & Brain Disorders, Dept Neurol, Hefei, Peoples R China
USTC, Affiliated Hosp 1, Hefei, Peoples R China
Pérez-Pérez, J:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Hosp Santa Creu i St Pau, Neurol Dept, Movement Disorders Unit, Barcelona, Spain
Biomed Res Inst St Pau IIB St Pau, Barcelona, Spain
Kulisevsky, J:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Hosp Santa Creu i St Pau, Neurol Dept, Movement Disorders Unit, Barcelona, Spain
Biomed Res Inst St Pau IIB St Pau, Barcelona, Spain
Autonomous Univ Barcelona, Dept Med, Barcelona, Spain
European Huntingtons Dis Network EHDN, Barcelona, Spain
Cuchillo-Ibáñez, I:
Univ Miguel Hernandez, Inst Neurociencias Alicante, CSIC, Sant Joan Dalacant, Alicante, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Inst Invest Sanitaria & Biomed Alicante ISABIAL Al, Alicante, Spain
Sáez-Valero, J:
Univ Miguel Hernandez, Inst Neurociencias Alicante, CSIC, Sant Joan Dalacant, Alicante, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Inst Invest Sanitaria & Biomed Alicante ISABIAL Al, Alicante, Spain
Green Accepted, Green Submitted, hybrid
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