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

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.

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

“…On the other hand, the compensatory upregulation of autophagic flux as observed in many diseases may become uncontrolled leading to detrimental consequences besides initial cytoprotective effects. Increased understanding of the role of autophagy in many diseases, including common neurodegenerative diseases such as Alzheimer's or Parkinson's disease, has led to an interest in pharmacological-or gene therapy-based approaches to modulate autophagy [1][2][3]78,79 (Figure 7). Because of similar changes in the autophagic pathway in pediatric brain diseases, related approaches could possibly be applied, for example, inhibiting autophagy in NP-C to ameliorate the induction of defective autophagy or enhancing autophagic flux in LD where a block in autophagosome has been described.…”

“…Crosstalk is of outmost importance for neurodegenerative diseases where a primary failure of degradation mechanisms has been proposed. [1][2][3][14][15][16] Dysfunction of autophagy can result from a block at every level of the pathway (Figure 2). With regards to neuronal pathology, defects in the autophagy pathway can be divided into those that cause impaired autophagic turnover and those that result in deregulated and overactive autophagy.…”

“…Accumulation of proteins, polysaccharides, and lipids are common mechanisms shared by major adult-onset neurodegenerative diseases [1][2][3] and many neurodegenerative diseases of childhood. 4 These conditions are, therefore, often referred to as "storage diseases" or "proteinopathies. "…”

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

“…A specific E3 ubiquitin ligase, Axotropin/MARCH7, has been identified in a yeast two-hybrid screen and shown to impair binding of the modified tau to microtubules [54]. Whilst only four lysine residues of tau were found to be ubiquitinated in paired helical filaments of human tau [11], a recent work detected 15 residues in wild-type mouse tau [21]. The discrepancy may be partly due to the fact that most of the lysine residues reported in the latter work are also subject to other modifications, i.e.…”

“…Some of the cellular structures and proteins for which interaction of the respective domains has been suggested are designated by the arrows shown below. This scheme summarizes informations from several excellent reviews, from which more detailed descriptions of the different modifications and their effect on tau in addition to those mentioned in the text can be obtained: [8,9,10,11,12]. (B) Different oligomerization states of tau are shown.…”