The Role of Cathepsin D in the Pathogenesis of Human Neurodegenerative Disorders

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.

Long-Term Assessment of AAV-Mediated Zinc Finger Nuclease Expression in the Mouse Brain

“…The ZFN pair was designed to cleave the murine cathepsin D (CatD) gene. CatD is the cell’s major ubiquitous lysosomal protease (Benes et al, 2008), and impaired protein degradation is intimately linked to neuronal disorders like Alzheimer’s and Parkinson’s disease (Cullen et al, 2009; Tian et al, 2014; Vidoni et al, 2016). The potential contribution of CatD to neurodegenerative disorders could not yet be studied in detail, however, as conventional CatD KO animals die at very early age due to severe visceral phenotypes, especially in the immune system (Saftig et al, 1995).…”

Regulation of cathepsin D activity by the FTLD protein progranulin

“…Cathepsin D (CTSD) is a lysosomal aspartic-type protease involved in many neurodegenerative diseases [14]. Mutations in the cathepsin D gene ( CTSD ) result in NCL in humans [9].…”

“…CTSD mediated proteolysis is essential to neuronal cell homeostasis through the degradation of aggregates delivered to lysosomes via autophagy or endocytosis [14]. Therefore by regulating CTSD activity, PGRN may modulate protein homeostasis.…”

Identification of Cerebral Metal Ion Imbalance in the Brain of Aging Octodon degus

“…Abnormalities in the lysosomal pathway have been previously reported in AD pathology, prior to the development of NFTs or Aβ plaques (Cataldo and Nixon, 1990; Cataldo et al, 1994). Since proteolytic processing of APP is necessary for the formation of Aβ, lysosomal proteases have been linked with AD pathology (Vidoni et al, 2016). The increased expression of cathepsin D reported in this study may represent a compensatory mechanism to restore lysosomal function (Perez et al, 2015).…”