Impairment of the Ubiquitin Proteasome Pathway in Aging and Neurodegeneration
The ubiquitin-proteasome system acts to degrade damaged and unwanted proteins, breaking them down to constituent parts that can be recycled. Ubiquitin is used to tag proteins designated for recycling, and these are drawn into the proteasome structure to be dismantled. There is some evidence for the activity of the proteasome to decline with age, but it isn't as clear-cut as the evidence for autophagy to falter. To the degree that proteasomal activity does decline, this may be a matter of reduced expression of important component parts of the proteasome, given that increasing expression of some component proteins can improve proteasomal function, or something more complex, such as impairment of the ability of proteasomes to move around the cell. These are proximate causes, and, as is often the case, it is very unclear as to how they relate to the underlying damage that causes aging.
Ubiquitin has long been known to be associated with pathologies of the brain, including that of Alzheimer's disease (AD). Our understanding of the link between ubiquitin-mediated proteolysis and neurodegenerative diseases such as AD, however, has only begun to improve with the elucidation of the mechanistic details of protein degradation. Although proteolysis by the ubiquitin-proteasome pathway (UPP) was originally assumed to operate only on abnormal proteins, research over many years has shown physiological roles for the UPP in various cells, including neurons. Several cellular functions are altered with aging. It is reasonable to hypothesize that ubiquitin-proteasome-mediated proteolysis is also impaired with aging. Investigations, however, have not yielded consistent results.
It is generally accepted that two main types of pathological phenomena occur in the AD brain. One is the accumulation of amyloid β (Aβ), the clumps of which lead to the development of plaques. The second is the accumulation of phosphorylated microtubule-associated protein tau, which ultimately forms tangles. The UPP is linked to both of these pathways of AD pathogenesis. In AD, ubiquitinated proteins accumulate, and it is believed that the proteolytic system in neurons is overwhelmed by aggregating proteins. Based on this logic, investigations were made of the proteasome in both postmortem human AD brains and in the brains of AD model mice. Studies found that proteasome activation by rolipram - a phosphodiesterase 4 (PDE4) inhibitor - decreased tau levels and improved cognition.
Improving the function of UPP components should, in principle, ameliorate some of the symptoms of AD. Because synaptic dysfunction and cognitive impairment are seen early in AD and the UPP has a role in synaptic plasticity and memory, it might be possible to manipulate the UPP to rescue some deficits. Based on the research thus far, there is no clear-cut relationship between aging and impairment of the proteasome function. When individual molecules are studied, however, a clearer picture emerges. In investigating the connections between the UPP and AD, many studies have focused on transgenic mouse models of AD based on the familial form of the human disease. These models were mainly based on the "Aβ hypothesis" of AD. Because the link of the UPP to AD is not just through Aβ, it would be worth investigating how the UPP relates to other factors contributing to AD such as insulin resistance and inflammation in the brain.