Ubiquitin/proteasome pathway impairment in neurodegeneration: therapeutic implications

Abstract

The ubiquitin/proteasome pathway is the major proteolytic quality control system in cells. In this review we discuss the impact of a deregulation of this pathway on neuronal function and its causal relationship to the intracellular deposition of ubiquitin protein conjugates in pathological inclusion bodies in all the major chronic neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's diseases as well as amyotrophic lateral sclerosis. We describe the intricate nature of the ubiquitin/proteasome pathway and discuss the paradox of protein aggregation, i.e. its potential toxic/protective effect in neurodegeneration. The relations between some of the dysfunctional components of the pathway and neurodegeneration are presented. We highlight possible ubiquitin/ proteasome pathway-targeting therapeutic approaches, such as activating the proteasome, enhancing ubiquitination and promoting SUMOylation that might be important to slow/treat the progression of neurodegeneration. Finally, a model time line is presented for neurodegeneration starting at the initial injurious events up to protein aggregation and cell death, with potential time points for therapeutic intervention.

Stimuli-responsive electrospun fibers and their applications

“…the detection of mutant proteins associated with neurodegenerative diseases like Alzheimer's, Huntington's or Pakinson's disease. 86,87 To this end, a lot of effort is put in optimizing the sensitivity of protein detection, e.g. by developing novel staining techniques for Western blots 88 or by introducing completely new detection methods based on, as an example, gold nanoparticles.…”

Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria

“…Furthermore, such long-term unspecific inhibition of abnormal protein degradation could lead to serious adverse toxic effects, especially in the central nervous system, and would not constitute a safe therapeutic choice for CEP (16,28). Recently, mutations in genes involved in the ubiquitin-proteasome system have been associated with the pathogenesis of neurodegenerative and other brain diseases (29).…”

Study into molecular targets of a neuroprotective compound dimebon using a transgenic mice line

“…Патологическая агрегация белков -процесс, имеющий место при ряде нейродегенеративных расстройств и потенциальная мишень для терапевтического воздействия, привлекательная своей универсальностью. Разработка препаратов, способных препятствовать образованию агрегированных патогенных форм белков или активировать внутриклеточные защитные системы, осуществляющие контролируемую деградацию патогенных продуктов белковой агрегации, сегодня по праву считается одним из наиболее перспективных подходов к предупреждению и коррекции подобных заболеваний [5][6][7]. При этом, использование линий трансгенных животных позволяет оптимизировать исследования по разработке и изучению такого типа нейропротекторных лекарственных средств.…”