Dysfunction of the Endosomal Na+/H+ Exchanger 6 (NHE6) in Cellular Models of Corticobasal Syndrome

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URI: http://hdl.handle.net/10900/101458
http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-1014588
http://dx.doi.org/10.15496/publikation-42837
Dokumentart: Dissertation
Date: 2022-05-19
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biologie
Advisor: Krüger, Rejko (Prof. Dr.)
Day of Oral Examination: 2020-05-19
DDC Classifikation: 000 - Computer science, information and general works
500 - Natural sciences and mathematics
570 - Life sciences; biology
610 - Medicine and health
Keywords: Endosom , Lysosom
Other Keywords:
endosome
lysosome
NHE6
SLC9A6
Corticobasal syndrome
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Inhaltszusammenfassung:

Dissertation ist gesperrt bis 19. Mai 2022 !

Abstract:

Corticobasal syndrome (CBS) is a neurodegenerative disease with the main symptoms including parkinsonism and frontotemporal dementia. The most common pathology underlying the disease is corticobasal degeneration (CBD), where hyperphosphorylated forms of the microtubule-associated protein tau accumulate. A common occurance in many neurodegenerative diseases is a dysfunction of the endosomal-lysosomal system including defects in receptor recycling and autophagic removal of defective organelles. In 2013, Riess et al. identified a mutation in the SLC9A6 gene coding for the endosomal cation exchanger 6 (NHE6) in a family with rare X-linked mental retardation in male members of the family. The grandmother of the index patient was subsequently shown to suffer from CBS and the work presented in the talk investigated the consequences of a loss of NHE6 in cellular models of the disease. NHE6 is involved in the regulating of the pH of the endosomal-lysosomal system. In line with this, an impairment of NHE6 function caused hyper-acidification across the endosomal-lysosomal system, affected endosomal maturation and led to impairments in autophagy. Using an inducible knockdown model in neuronal cancer cells, an increase in the phosphorylation of tau could be shown, and insoluble tau accumulated differently in brain tissue obtained from CBS patients with a variant in the SLC9A6 gene. In summary, NHE6 loss of function deregulates endosomal-lysosomal pH, impacts the endosomal-lysosomal system, autophagy and tau status, and could prove a valuable target for study in CBS and other tau-related neurodegenerative diseases.

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