Role of lysosomal integral membrane protein type 2 (LIMP2) in neuronal endolysosomal trafficking and its relevance in Gaucher disease type 2

Simple item page
dc.catalogadoraba
dc.contributor.advisorZanlungo Matsuhiro, Silvana
dc.contributor.advisorÁlvarez Rojas, Alejandra
dc.contributor.authorArévalo Ramírez, Nohela Betzabeth
dc.contributor.otherPontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas
dc.date2026-04-23
dc.date.accessioned2025-04-28T13:54:55Z
dc.date.available2025-04-28T13:54:55Z
dc.date.issued2025
dc.date.updated2025-04-22T17:11:20Z
dc.descriptionTesis (Doctor of Biological Sciences)--Pontificia Universidad Católica de Chile, 2025
dc.descriptionTESIS EMBARGADA POR LA ALUMNA HASTA EL 22 DE ABRIL DE 2026
dc.description.abstractBackground: Gaucher disease type 2 (GD2) is a neuronopathic acute lysosomal storage disease (LSD) caused by mutations in the GBA1 gene, which lead to the loss of β-Glucocerebrosidase (β-GC) lysosomal activity. This enzymatic deficiency triggers the accumulation of glucosylceramide (GluCer) in the lysosomes, mainly in macrophages and neurons. In GD2 neurons, synaptic alterations, neuroinflammation, and neuronal loss have been described, yet the underlying mechanisms remain unclear. Recently, an altered distribution of LIMP2+ structures that preceded neuroinflammation and neuronal loss was reported in GD2 models, suggesting the role of LIMP2 in pathology. LIMP2 is a lysosomal integral membrane protein and the only β-GC transporter described. However, current literature has pointed out the pivotal role of LIMP2 in endolysosomal biogenesis and trafficking. We wonder if LIMP2 alterations in GD2 could impact endolysosomal homeostasis and if these defects could be associated with synaptic dysfunction in GD2 pharmacological models. Aim: To characterize LIMP2 alterations and their impact on endolysosomal trafficking and their association with modifications in synaptic parameters in GD2. Results: GD2 models, including mice and hippocampal neurons treated with CβE, showed increased LIMP2 protein levels compared to controls. Interestingly, these models also exhibited aberrant LIMP2+ tubular structures that were not found in control models or other LSDs. We identify these structures as endolysosomal compartments based on their colocalization with LAMP1, LAMTOR4, and SirLyso. Furthermore, these structures colocalize with VTi1B and likely with LC3 and clathrin. These proteins, along with LIMP2, are involved in autophagy and lysophagy. Due to tubular morphology and the association with these markers, we propose that these aberrant endolysosomal compartments may arise from defects in lysosomal reformation. Besides, GD2 hippocampal neurons displayed an altered endolysosomal dynamics with a global decrease of fusion, fission, and kiss & run events. Alterations in endolysosomal structures and dynamics occurred in parallel with changes in post-synaptic parameters, such as downregulation of NR2B, PSD95, and HOMER protein levels in hippocampal neurons and a decrease in the number of post-synaptic densities (PSD) in the cortex of CβE-treated mice. Conclusions: We report the presence of aberrant endolysosomal compartments that are unique to the GD2 phenotype. Moreover, these structures may be closely related to defects in lysosomal reformation, either from autophagy or lysophagy. Furthermore, an alteration of endolysosomal dynamics could be associated with the origin of these structures and could impact other cellular processes, such as cellular trafficking. Together with the changes in endolysosomal homeostasis, the GD2 context is characterized by changes in post-synaptic components. Given the essential role of the endolysosomal system in synaptic function and maintenance, our findings highlight that there could exist a potential link between endolysosomal alterations and synaptic dysfunction. A deeper understanding of this relationship is essential to uncover pathological mechanisms involved in the GD2 context.
dc.description.funderFondef
dc.description.funderCorfo
dc.description.funderFundación Copec UC
dc.fechaingreso.objetodigital2025-04-28
dc.fuente.origenAutoarchivo
dc.identifier.doi10.7764/tesisUC/BIO/103476
dc.identifier.urihttps://doi.org/10.7764/tesisUC/BIO/103476
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/103476
dc.information.autorucEscuela de Medicina; Zanlungo Matsuhiro, Silvana; 0000-0001-8383-9829; 72650
dc.information.autorucFacultad de Ciencias Biológicas; Álvarez Rojas, Alejandra; 0000-0002-8129-9280; 83681
dc.information.autorucFacultad de Ciencias Biológicas; Arévalo Ramírez, Nohela Betzabeth; S/I; 1132058
dc.language.isoen
dc.nota.accesocontenido completo
dc.rightsacceso embargado
dc.rights.licenseAtribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject.ddc570
dc.subject.deweyBiologíaes_ES
dc.subject.ods03 Good health and well-being
dc.subject.odspa03 Salud y bienestar
dc.titleRole of lysosomal integral membrane protein type 2 (LIMP2) in neuronal endolysosomal trafficking and its relevance in Gaucher disease type 2
dc.typetesis doctoral
sipa.codpersvinculados72650
sipa.codpersvinculados83681
sipa.codpersvinculados1132058
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Role of lysosomal integral membrane protein type 2 (LIMP2) in neuronal endolysosomal trafficking and its relevance in Gaucher disease type 2.pdf
Size:
5.23 MB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
1.98 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Material embargado