Inhibitors of Lysosomal Enzymes: Accumulation of Lipofuscin-Like Dense Bodies in the Brain

Ivy, GO; Schottler, Frank; Wenzel, J; Baudry, Michael; Lynch, Gary

doi:10.1126/science.6505679

Cited by 266 publications

(105 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is the formation of lipofuscin-like lipopigments in rat hepatocytes and other internal organs, such as kidneys, following an intraperitoneal administration of protease inhibitors, such as leupeptin (Ivy et al , 1991a. This observation strongly supports the idea that the perturbation of protein degradation and its intracellular disposition in secondary lysosomes is a fundamental mechanism for lipofuscinogenesis, as Ivy initially proposed for brain cells 20 years ago (Ivy et al 1984). At the same time, this observation strongly suggests that a decrease in proteolysis during aging leads to progressive decreases in turnovers of intracellular proteins, including enzyme molecules.…”

Section: What Really Declines With Age?supporting

confidence: 59%

What really declines with age?

Kitani¹

2007

AGE

View full text Add to dashboard Cite

In order to understand the basic mechanisms underlying the organismic aging process, considerable efforts have been devoted in the last half-century to biochemical (enzyme activity) alterations in specific tissues and organs of various organisms associated with aging. When a decline in enzyme activities with age has been found in a study, especially for key enzymes such as antioxidant enzymes, the results have often been interpreted as a cause for the aging of the entire body. Retrospectively, however, these changes turned out to be so variabledepending on species, strains and sexes of animalsthat the interpretation of these results in general terms of aging became invalid. Further, unlike the prediction for the whole human body, many enzyme activities in a vital organ, such as the liver, remained unchanged, as long as the old subjects remained healthy. However, enzyme activities in old animals and humans are often more susceptible to morbidities and frailties, which themselves are often accompanied by infections and malnutrition. Despite the rather stable enzyme functions in the liver with age, a distinct and progressive decline in the lateral diffusion coefficient of proteins of hepatocyte plasma membranes has been demonstrated by fluorescence recovery after photobleaching (FRAP), which was implicated as the cause for the decline of hepatocyte functions such as ouabain (and taurocholate) hepatic uptake and their eventual biliary excretion. Since a similar decline in protein diffusion coefficients was observed in brain and muscle cells, it is likely that these changes are occurring in common with many cell types of the body, thus causing a delay in transmembrane transport of endogenous and exogenous substances whose transports are mediated by membrane proteins. In attempts to prolong the life spans of animals other than by calorie restriction, but instead using deprenyl or tetrahydrocurcumin, works by the author and coworkers are introduced and discussed. Despite limited success along these lines thus far, further attempts are encouraged, primarily to understand the mechanisms underlying organismic aging processes and to find a practical way to prolong the health span of the elderly.

show abstract

Section: What Really Declines With Age?supporting

confidence: 59%

What really declines with age?

Kitani¹

2007

AGE

View full text Add to dashboard Cite

show abstract

“…Intraventricular infusions of the broad-spectrum serine and cysteine protease inhibitor leupeptin and the cysteine protease inhibitor E-64c resulted in a general accumulation of dense granular aggregates throughout rodent brains, as well as in the retina and internal organs, thereby partially reproducing features of NCLs, Alzheimer's disease, and aging (41). Several in vitro studies using cultured hippocampal and cortical slices (42,43) or cardiac myocytes (44) appeared to reproduce the in vivo experiments.…”

Section: Discussionmentioning

confidence: 78%

Neuronal loss and brain atrophy in mice lacking cathepsins B and L

Felbor

Kessler²,

Mothes³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

307

217

View full text Add to dashboard Cite

Cathepsins B and L are widely expressed cysteine proteases implicated in both intracellular proteolysis and extracellular matrix remodeling. However, specific roles remain to be validated in vivo. Here we show that combined deficiency of cathepsins B and L in mice is lethal during the second to fourth week of life. Cathepsin B ؊/؊ ͞L ؊/؊ mice reveal a degree of brain atrophy not previously seen in mice. This is because of massive apoptosis of select neurons in the cerebral cortex and the cerebellar Purkinje and granule cell layers. Neurodegeneration is accompanied by pronounced reactive astrocytosis and is preceded by an accumulation of ultrastructurally and biochemically unique lysosomal bodies in large cortical neurons and by axonal enlargements. Our data demonstrate a pivotal role for cathepsins B and L in maintenance of the central nervous system.

show abstract

“…Alterations in the last step of autophagy—the degradation of cargo in the lysosomal lumen (Hayasaka, 1989; Ivy, Schottler, Wenzel, Baudry & Lynch, 1984; Nakano, Oenzil, Mizuno & Gotoh, 1995; Tauchi, Hananouchi & Sato, 1980)—and reduced autophagosome/lysosome fusion have both shown to contribute to autophagic failure in the old liver (Terman, 1995). Although the extensive changes in the lipid composition of intracellular membranes reported in old cells (Kitani, 1999; Rottem & Greenberg, 1975) lead to the proposal that reduced vesicle fusogenicity was behind autophagosome maturation, our studies with isolated autophagosomes and lysosomes reveal that fusion between these two compartments is actually enhanced and not reduced.…”

Section: Discussionmentioning

confidence: 99%

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

et al. 2018

View full text Add to dashboard Cite

SummaryInability to preserve proteostasis with age contributes to the gradual loss of function that characterizes old organisms. Defective autophagy, a component of the proteostasis network for delivery and degradation of intracellular materials in lysosomes, has been described in multiple old organisms, while a robust autophagy response has been linked to longevity. The molecular mechanisms responsible for defective autophagic function with age remain, for the most part, poorly characterized. In this work, we have identified differences between young and old cells in the intracellular trafficking of the vesicular compartments that participate in autophagy. Failure to reposition autophagosomes and lysosomes toward the perinuclear region with age reduces the efficiency of their fusion and the subsequent degradation of the sequestered cargo. Hepatocytes from old mice display lower association of two microtubule‐based minus‐end‐directed motor proteins, the well‐characterized dynein, and the less‐studied KIFC3, with autophagosomes and lysosomes, respectively. Using genetic approaches to mimic the lower levels of KIFC3 observed in old cells, we confirmed that reduced content of this motor protein in fibroblasts leads to failed lysosomal repositioning and diminished autophagic flux. Our study connects defects in intracellular trafficking with insufficient autophagy in old organisms and identifies motor proteins as a novel target for future interventions aiming at correcting autophagic activity with anti‐aging purposes.

show abstract

Inhibitors of Lysosomal Enzymes: Accumulation of Lipofuscin-Like Dense Bodies in the Brain

Cited by 266 publications

References 19 publications

What really declines with age?

What really declines with age?

Neuronal loss and brain atrophy in mice lacking cathepsins B and L

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

Contact Info

Product

Resources

About