Vidoni, C., Follo, C., Savino, M., Melone, M.A.B., Isidoro, C.
The Role of Cathepsin D in the Pathogenesis of Human Neurodegenerative Disorders
(2016) Medicinal Research Reviews, 36 (5), pp. 845-870.
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84981543795&partnerID=40&md5=01ab24566520bf8271425538ffe3a2dc
DOI: 10.1002/med.21394
AFFILIATIONS: Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro,”, Novara, Italy;
Division of Neurology, Department of Clinic and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy;
InterUniversity Center for Research in Neurosciences, Second University of Naples, Naples, Italy;
San Francisco General Hospital, University of California San Francisco, San Francisco, CA, United States
ABSTRACT: In familial neurodegenerative disorders, protein aggregates form continuously because of genetic mutations that drive the synthesis of truncated or unfolded proteins. The oxidative stress imposed by neurotransmitters and environmental neurotoxins constitutes an additional threat to the folding of the proteins and the integrity of organelle membranes in neurons. Failure in degrading such altered materials compromises the function of neurons and eventually leads to neurodegeneration. The lysosomal proteolytic enzyme Cathepsin D is the only aspartic-type protease ubiquitously expressed in all the cells of the human body, and it is expressed at high level in the brain. In general, cathepsin D mediated proteolysis is essential to neuronal cell homeostasis through the degradation of unfolded or oxidized protein aggregates delivered to lysosomes via autophagy or endocytosis. More specifically, many altered neuronal proteins that hallmark neurodegenerative diseases (e.g., the amyloid precursor, α-synuclein, and huntingtin) are physiologic substrates of cathepsin D and would abnormally accumulate if not efficiently degraded by this enzyme. Furthermore, experimental evidence indicates that cathepsin D activity is linked to the metabolism of cholesterol and of glycosaminoglycans, which accounts for its involvement in neuronal plasticity. This review focuses on the unique role of cathepsin D mediated proteolysis in the pathogenesis of human neurodegenerative diseases. © 2016 Wiley Periodicals, Inc.
CORRESPONDENCE ADDRESS: Isidoro, C.; Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro,”Italy; email: ciro.isidoro@med.uniupo.it
DOCUMENT TYPE: Review
