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LECTURE: Endosomal pH as a Therapeutic Target for Neurodegenerative Disease


 Rajini Rao, Ph.D.

Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, USA

Dysregulation of endo-lysosomal pH has been linked to aging, amyloidogenesis, synaptic dysfunction, and various neurodegenerative disorders including Alzheimer’s disease. Therefore, understanding mechanisms that regulate luminal pH is key to identifying new targets for treatment of these disorders. By functioning as a leak pathway for protons, the Christianson syndrome protein Na+/H+ Exchanger Isoform 6, NHE6, limits luminal acidification in the endosomes of neurons and glial cells. We show that alkalization of endosomes by NHE6 activity blocks retrograde trafficking of amyloid precursor protein (APP) from endosomes to the trans-Golgi network. Loss of NHE6 significantly increases harmful APP processing and amyloid Aβ secretion. Furthermore, NHE6 promotes astrocytic Aβ clearance by regulating recycling and surface expression of low-density lipoprotein receptor-related protein 1 (LRP1) in disease-associated ApoE4 variants. Our observations from yeast and other model organisms reveal an evolutionarily conserved mechanism for regulation of endosomal Na+/H+ exchangers by histone deacetylases and offer new therapeutic strategies for modulation of endo-lysosomal pH in fungal infection and human disease.

 

Výsledek obrázku pro rajini rao

 

Kontaktní osoba v FGÚ: Olga Zimmermannova, Olga.Zimmermannova@fgu.cas.cz