Proteostasis in Parkinson?s disease: Recent development and possible implication in diagnosis and therapeutics

The protein dyshomeostasis is identified as the hallmark of many age-related neurodegenerative disorders including Parkinson's disease (PD). The diseased brain shows the deposition of Lewy bodies composed of alpha-synuclein protein aggregates. Functional proteostasis is characterized by the well-coordinated signaling network constituting unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and the autophagy-lysosome pathway (ALP). These networks ensure proper synthesis, folding, confirmation, and degradation of protein i.e., alpha-synuclein protein in PD. The proper functioning the of intricately woven proteostasis network is quite resilient to sustain under the influence of stressors. The synuclein protein turnover is hugely influenced by the autosomal dominant, recessive, and X-linked mutational changes of a gene involved in UPR, UPS, and ALP. The methylation, acetylation-related epigenetic modifications of DNA and histone proteins along with microRNA-mediated transcriptional changes also lead to extensive proteostasis dysregulation. The result of defective proteostasis is the deposition of many proteins which start appearing in the biofluids and can be identified as potential biomarkers for early diagnosis of PD. The therapeutic intervention targeted at different strata of proteostasis machinery holds great possibilities for delaying the age-related accumulation of pathological hallmarks.

Automated summary

Protein dyshomeostasis plays a key role in age-related neurodegenerative disorders, such as Parkinson's disease, characterized by the deposition of Lewy bodies composed of alpha-synuclein protein aggregates. The proper functioning of proteostasis, including unfolded protein response, ubiquitin-proteasome system, and autophagy-lysosome pathway, is crucial for protein synthesis, folding, confirmation, and degradation. Mutational changes in the genes involved in these pathways, as well as epigenetic modifications and microRNA-mediated transcriptional changes, contribute to proteostasis dysregulation. Defective proteostasis leads to the deposition of proteins, which can serve as potential biomarkers for early diagnosis of Parkinson's disease. Targeting different aspects of proteostasis machinery holds promise for delaying the accumulation of pathological hallmarks.