The Mechanistic Links Between Proteasome Activity, Aging and Age-related Diseases

Abstract

Damaged and misfolded proteins accumulate during the aging process, impairing cell function and tissue homeostasis. These perturbations to protein homeostasis (proteostasis) are hallmarks of age-related neurodegenerative disorders such as Alzheimer's, Parkinson's or Huntington's disease. Damaged proteins are degraded by cellular clearance mechanisms such as the proteasome, a key component of the proteostasis network. Proteasome activity declines during aging, and proteasomal dysfunction is associated with late-onset disorders. Modulation of proteasome activity extends lifespan and protects organisms from symptoms associated with proteostasis disorders. Here we review the links between proteasome activity, aging and neurodegeneration. Additionally, strategies to modulate proteasome activity and delay the onset of diseases associated to proteasomal dysfunction are discussed herein.

Keywords: Aging; Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; Proteasome; Proteostasis; Stem cells..

Fig. (1)

The Ubiquitin-Proteasome System (UPS). Ubiquitin is activated through the ubiquitin-activating enzyme (E1) and next transferred to the ubiquitin-conjugating enzyme (E2). Both E2 and the target protein bind to the ubiquitin-ligase (E3) which links the activated ubiquitin from E2 to the target protein. The sequential conjugation of ubiquitins to the target protein generates a poly-ubiquitin chain, which acts as a signal for the protein to be degraded through the proteasome. Active proteasomes are formed by the interaction of proteasomal regulatory particles with a core particle (20S), which contains the proteolytic active sites. Free intracellular 20S are normally found in an inactive/closed state and require the binding of 20S activators to degrade proteins. The major assembly of the 20S proteasome is with the 19S regulatory protein, which recognizes the polyubiquitylated substrate, removes the ubiquitin moieties and unfolds the substrate to translocate it into the 20S proteolytic chamber. The 20S can also be activated by the PA28 complex (also known as 11S) or by the Blm10/PA200 protein. Finally, the protein is cleaved into short peptides. The proteasome is involved in a variety of cellular functions, such as quality control of the proteome, stress response or cell cycle regulation.

Fig. (2)

The links between proteasome activity, aging and age-related diseases. a, Human embryonic stem cells (hESCs) exhibit higher levels of proteasome activity than their differentiated counterparts (i.e. fibroblasts, trophoblasts or neurons). This high activity is required for the maintenance of stem cell function and is mediated, among others, through increased expression of the 19S proteasomal subunit Rpn6. b, Proteasome activity declines with aging as a consequence of a reduction in the expression of proteasomal subunits, alteration or replacement of several proteasomal subunits, disassembly of the proteasome or inactivation of the proteasome through direct interaction with age-induced protein-aggregates. Consequently, interventions that increase and sustain proteasome activity such as overexpression of proteasomal subunits and chaperones can extend lifespan and delay the onset of age-related diseases. Several longevity-promoting pathways (i.e., dietary restriction (DR) or reduced insulin/IGF-1 signaling pathway (IIS)) increase proteasome activity. Likewise, long-lived organisms (i.e., the naked mole rat and the giant clam) and centenarians exhibit increased proteasome activity.