Targeting an Improvement in Protein Quality Control
A range of research efforts aim at finding ways to improve or enhance the activity of cellular maintenance mechanisms involved in ensuring quality control. Proteins are the building blocks of cell machinery but constantly become damaged or misfolded, which can then cause harm through incorrect function. Thus cells work hard to clear out, break down, and recycle these problem molecules, but all of these mechanisms decline with aging; based on what we know to date, this happens because the repair machinery itself is vulnerable to forms of damage or can be negatively impacted by reactions to damage taking place in other processes, just like the rest of a cell.
So far there is little concrete progress towards therapies based on enhanced protein quality control, though a variety of genetic alterations that extend life in laboratory animals are shown to include enhanced quality control as a part of their effects. I would expect some candidate therapies to emerge in the years ahead, however, as the interest in moving in that direction certainly exists:
Impairment of "protein quality control" in neurons is associated with the etiology and pathogenesis of neurodegenerative diseases. The worn-out products of cell metabolism should be safely eliminated via the proteasome, autophago-lysosome and exocytosis. Insufficient activity of these degradation mechanisms within neurons leads to the accumulation of toxic protein oligomers, which represent a starting material for development of neurodegenerative proteinopathy.The spectrum of CNS linked proteinopathies is particularly broad and includes Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia, Pick disease, Frontotemporal dementia, Huntington disease, Amyotrophic lateral sclerosis and many others. Although the primary events in etiology and pathogenesis of sporadic forms of these diseases are still unknown, it is clear that aging, in connection with decreased activity of ubiquitin proteasome system, is the most significant risk factor.
We discuss the pathogenic role and intracellular fate of the candidate molecules associated with onset and progression of AD and PD, the protein tau and α-synuclein in context with the function of ubiquitin proteasome system. We also discuss the possibility whether or not the strategies focused to re-establishment of neuroproteostasis via accelerated clearance of damaged proteins in proteasome could be a promising therapeutic approach for treatment of major neurodegenerative diseases.