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The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease

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The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease

Yasuo Ihara et al. Cold Spring Harb Perspect Med.

Abstract

As neurons age, their survival depends on eliminating a growing burden of damaged, potentially toxic proteins and organelles-a capability that declines owing to aging and disease factors. Here, we review the two proteolytic systems principally responsible for protein quality control in neurons and their important contributions to Alzheimer disease pathogenesis. In the first section, the discovery of paired helical filament ubiquitination is described as a backdrop for discussing the importance of the ubiquitin-proteasome system in Alzheimer disease. In the second section, we review the prominent involvement of the lysosomal system beginning with pathological endosomal-lysosomal activation and signaling at the very earliest stages of Alzheimer disease followed by the progressive failure of autophagy. These abnormalities, which result in part from Alzheimer-related genes acting directly on these lysosomal pathways, contribute to the development of each of the Alzheimer neuropathological hallmarks and represent a promising therapeutic target.

Figures

Figure 1.
Figure 1.
DF2 immunostaining of a tissue section from Alzheimer disease (AD) hippocampus. Neurofibrillary tangles and dystrophic neurites (arrowhead) are intensely labeled, whereas the neuropil (background) is uniformly stained, simulating nonspecific background staining. However, this was found to be true staining of ubiquitin-conjugated proteins in the neuropil (Morimoto et al. 1996). (Inset) Some neurons in CA1 undergo granulovacuolar changes (arrows) and are also intensely stained with DF2.
Figure 2.
Figure 2.
Schematic illustration of 76-residue ubiquitin. Ubiquitin has seven lysine residues and Achromobacter lyticus protease 1 (AP1) cleaves ubiquitin into eight fragments, U1–U8. G76 is conjugated with ε-amino groups of lysine in the target protein. K48-linked ubiquitin chain is a strong degradation signal. Besides this, K6-, 11-, 27-, 29-, and 63-linked multiubiquitin chains are found in the cell (Xu and Peng 2006). It is likely that each type of chain has a distinct role in the cellular metabolism.
Figure 3.
Figure 3.
Ubiquitination sites on amino terminally processed tau. As shown in A, four ubiquitin conjugation sites were identified. These are located close to and in the microtubule-binding domain, K254, 257, 311, and 317 according to the numbering of the 441 amino acid human tau isoform. A size exclusion–purified paired helical filament PHF smear was further purified by reverse-phase HPLC, giving three broad (overlapped) peaks that existed only in smear fractions from AD brain. The last-eluting fraction contained a ubiquitin (Ub)-positive, tau-positive smear, which was subjected to AP1 digestion and reverse HPLC fractionation, followed by amino acid sequencing and mass spectrometric analysis. Several late-eluting peaks were found to contain branched fragments, mostly consisting of tau fragments and U8; a minority of U8 conjugated with Lys-48 of U6–U7, derived from the polyubiquitin chain (Morishima-Kawashima et al. 1993). Dysfunction of autophagic and endocytic pathways to lysosomes driven by relevant genes and other risk factors in Alzheimer disease (expressed on the left side of the diagram) causes or promotes pathophysiology critical to the development and progression of the disease (outlined on the right side of the diagram). See the text for further details.
Figure 4.
Figure 4.
Schematic illustration of 26S proteasome. It consists of 19S regulatory particle (RP) and 20S core particle (CP). The narrow canal of CP consists of heptameric stacks of four rings, with the inner two being composed of β subunits and the outer two of α subunits. The image on the right shows a cross section at an indicated line (left). These subunits have trypsin-like, chymotrypsin-like, and peptidyl glutaminyl hydrolyzing activities. (Modified from Gallastegui and Groll 2010.)
Figure 5.
Figure 5.
Schematic illustrating the endocytic and the autophagic pathways to the lysosome. See the text for details.
Figure 6.
Figure 6.
Progression of pathological changes in the lysosomal network in Alzheimer disease (AD). A normal neuron is depicted in A. At the earliest stages of AD (B), accelerated endocytosis, mediated in part by βCTF and/or by pathological activation of rab5, causes endosome enlargement (D; rab5 immunocytochemistry), defective retrograde transport of endosomes and their neurotrophin cargoes, proapoptotic pathway activation, and cholinergic neurodegeneration. Initial up-regulation of lysosome biogenesis (E; cathepsin D immunocytochemistry) is followed by progressive failure of lysosomal proteolysis (C), which impedes autophagy and the axonal transport of late endosomes/MVBs and autophagy-related vesicular compartments. These compartments, containing incompletely digested protein substrates, selectively accumulate within neurons and especially dystrophic neurites (C), as depicted in F (LC3 immunocytochemistry) and G (ultrastructure of AVs in a dystrophic neurite). Failure of lysosomal proteolysis and autophagy in AD is caused by PS1 mutations in early-onset FAD and is also promoted by normal aging, oxidative stress, ApoE ε4, intracellular Aβ, and other AD-related genetic and environmental risk factors.
Figure 7.
Figure 7.
Dysfunction of autophagic and endocytic pathways to lysosomes driven by relevant genes and other risk factors in Alzheimer disease (left side of the diagram) causes or promotes pathophysiology critical to the development and progression of Alzheimer disease (right side of the diagram). See the text for further details.

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