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Autophagy failure inAlzheimer's diseaseand the role ofdefective lysosomalacidification Devin M. WolfeJu‐Hyun LeeAsok Kumar2013 год

Autophagy failure in Alzheimer's disease and the role of defective lysosomal acidification
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Аннотация: Abstract Autophagy is a lysosomal degradative process which recycles cellular waste and eliminates potentially toxic damaged organelles and protein aggregates. The important cytoprotective functions of autophagy are demonstrated by the diverse pathogenic consequences that may stem from autophagy dysregulation in a growing number of neurodegenerative disorders. In many of the diseases associated with autophagy anomalies, it is the final stage of autophagy–lysosomal degradation that is disrupted. In several disorders, including A lzheimer's disease ( AD ), defective lysosomal acidification contributes to this proteolytic failure. The complex regulation of lysosomal p H makes this process vulnerable to disruption by many factors, and reliable lysosomal p H measurements have become increasingly important in investigations of disease mechanisms. Although various reagents for p H quantification have been developed over several decades, they are not all equally well suited for measuring the p H of lysosomes. Here, we evaluate the most commonly used p H probes for sensitivity and localisation, and identify L yso S ensor yellow/blue‐dextran, among currently used probes, as having the optimal profile of properties for measuring lysosomal p H . In addition, we review evidence that lysosomal acidification is defective in AD and extend our original findings, of elevated lysosomal p H in presenilin 1 ( PS 1)‐deficient blastocysts and neurons, to additional cell models of PS 1 and PS 1/2 deficiency, to fibroblasts from AD patients with PS 1 mutations, and to neurons in the PS / APP mouse model of AD .
Год издания: 2013
Авторы: Devin M. Wolfe, Ju‐Hyun Lee, Asok Kumar, Sooyeon Lee, Samantha J. Orenstein, Ralph A. Nixon
Издательство: Wiley
Источник: European Journal of Neuroscience
Ключевые слова: Autophagy in Disease and Therapy, Lysosomal Storage Disorders Research, Calcium signaling and nucleotide metabolism
Другие ссылки: European Journal of Neuroscience (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
PubMed (HTML)