Cellular Responses to Protein Accumulation Involve Autophagy and Lysosomal Enzyme Activation

Abstract

Protein oligomerization and aggregation are key events in age-related neurodegenerative disorders, causing neuronal disturbances including microtubule destabilization, transport failure and loss of synaptic integrity that precede cell death. The abnormal buildup of proteins can overload digestive systems and this, in turn, activates lysosomes in different disease states and stimulates the inducible class of lysosomal protein degradation, macroautophagy. These responses were studied in a hippocampal slice model well known for amyloidogenic species, tau aggregates, and ubiquitinated proteins in response to chloroquine-mediated disruption of degradative processes. Chloroquine was found to cause a pronounced appearance of prelysosomal autophagic vacuoles in pyramidal neurons. The vacuoles and dense bodies were concentrated in the basal pole of neurons and in dystrophic neurites. In hippocampal slice cultures treated with Abeta(142), ultrastructural changes were also induced. Autophagic responses may be an attempt to compensate for protein accumulation, however, they were not sufficient to prevent axonopathy indicated by swellings, transport deficits, and reduced expression of synaptic components. Additional chloroquine effects included activation of cathepsin D and other lysosomal hydrolases. Abeta(142) produced similar lysosomal activation, and the effects of Abeta(142) and chloroquine were not additive, suggesting a common mechanism. Activated levels of cathepsin D were enhanced with the lysosomal modulator Z-Phe-Ala-diazomethylketone (PADK). PADK-mediated lysosomal enhancement corresponded with the restoration of synaptic markers, in association with stabilization of microtubules and transport capability. To show that PADK can modulate the lysosomal system in vivo, IP injections were administered over a 5-day period, resulting in a dose-dependent increase in lysosomal hydrolases. The findings indicate that degradative responses can be modulated to promote synaptic maintenance.

Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl–mediated drug resistance

“…The ability of CQ to promote increased cathepsin D expression has also been noted in an earlier investigation, yet our knockdown studies in LAMA 84 CML cells now establish that cathepsin D plays an essential role in the ability of CQ to potentiate the proapoptotic effects of SAHA and to degrade the cathepsin D substrate Trx. 48 Based on our studies, it also appears that druginduced modulation of cathepsin D expression underlies the increased activation of caspase-3 observed under combination conditions, since apoptosis induced by the CQ/SAHA combination is impaired by knockdown of cathepsin D.…”

“…The ability of CQ to promote increased cathepsin D expression has also been noted in an earlier investigation, yet our knockdown studies in LAMA 84 CML cells now establish that cathepsin D plays an essential role in the ability of CQ to potentiate the proapoptotic effects of SAHA and to degrade the cathepsin D substrate Trx. 48 Based on our studies, it also appears that druginduced modulation of cathepsin D expression underlies the increased activation of caspase-3 observed under combination conditions, since apoptosis induced by the CQ/SAHA combination is impaired by knockdown of cathepsin D.Equally striking are the effects of CQ and the CQ/SAHA combination on the subcellular localization of cathepsin D. Specifically, CQ treatment leads to a marked accumulation of cathepsin D into large aggregates that are not colocalized with lysosomes. Further, this response is augmented by SAHA, which as a single agent has limited effects on cathepsin D expression or localization.…”

Ginsenoside Rg1 protects mouse podocytes from aldosterone-induced injury in vitro

“…Increased expression of beclin-1 suggests the occurrence of autophagy, which may trigger a rapid autophagic response under stress conditions [20] . Pharmacological inhibitors of autophagy, such as 3-methyladenine (3-MA), chloroquine, and bafilomycin (BAF), induce cell apoptosis, implying that autophagy is cytoprotective in a variety of cell injury models [21] . At the early stage, autophagy is a protective mechanism that promotes cell survival.…”

Positive Lysosomal Modulation As a Unique Strategy to Treat Age-Related Protein Accumulation Diseases

“…In fact, a striking resemblance is apparent between the hippocampal slice model of protein accumulation and the Alzheimer disease brain regarding the loss of synaptic integrity as well as axonopathy and associated transport failure. [7][8][9] One of the earliest events linked to lysosomal disturbances is the reduction in pre-and postsynaptic markers. Synapses also experience dynamic changes in Alzheimer disease, with synaptic loss well established as the best neurobiological correlate of the cognitive deficits.…”