The term proteostasis reflects the fine-tuned balance of cellular protein levels, mediated through a vast network of biochemical pathways. This requires the regulated control of protein folding, post-translational modification, and protein degradation. Due to the complex interactions and intersection of proteostasis pathways, exposure to stress conditions may lead to a disruption of the entire network. Incorrect protein folding and/or modifications during protein synthesis results in inactive or toxic proteins, which may overload degradation mechanisms. Further, a disruption of autophagy and the endoplasmic reticulum degradation pathway may result in additional cellular stress which could ultimately lead to cell death. Neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis all share common risk factors such as oxidative stress, aging, environmental stress, and protein dysfunction; all of which alter cellular proteostasis. The differing pathologies observed in neurodegenerative diseases are determined by factors such as location-specific neuronal death, source of protein dysfunction, and the cell's ability to counter proteotoxicity. In this review, we discuss how the disruption in cellular proteostasis contributes to the onset and progression of neurodegenerative diseases.

The last decade has experienced the emergence of microRNAs as a key molecular tool for the diagnosis and prognosis of human diseases. Although the focus has mostly been on cancer, neurodegenerative diseases present an exciting, yet less explored, platform for microRNA research. Several studies have highlighted the significance of microRNAs in neurogenesis and neurodegeneration, and pre-clinical studies have shown the potential of microRNAs as biomarkers. Despite this, no bona fide microRNAs have been identified as true diagnostic or prognostic biomarkers for neurodegenerative disease. This is mainly due to the lack of precisely defined patient cohorts and the variability within and between individual cohorts. However, the discovery that microRNAs exist as stable molecules at detectable levels in body fluids has opened up new avenues for microRNAs as potential biomarker candidates. Furthermore, technological developments in microRNA biology have contributed to the possible design of microRNA-mediated disease intervention strategies. The combination of these advancements, with the availability of well-defined longitudinal patient cohort, promises to not only assist in developing invaluable diagnostic tools for clinicians, but also to increase our overall understanding of the underlying heterogeneity of neurodegenerative diseases. In this review, we present a comprehensive overview of the existing knowledge of microRNAs in neurodegeneration and provide a perspective of the applicability of microRNAs as a basis for future therapeutic intervention strategies.

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MicroRNAs are key regulators associated with numerous diseases. In HEK293 cells, miR-153-3p and miR-205-5p down-regulate alpha-synuclein (SNCA) and Leucine-rich repeat kinase 2 (LRRK2), two key proteins involved in Parkinson’s disease (PD). We have used two-dimensional gel electrophoresis (2D-PAGE) coupled to mass spectrometry (MS) to identify a spectrum of miR-153-3p and miR-205-5p targets in neuronal SH-SY5Y cells. We overexpressed and inhibited both microRNAs in SH-SY5Y cells and through comparative proteomics profiling we quantified ~240 protein spots from each analysis. Combined, thirty-three protein spots were identified showing significant (p-value < 0.05) changes in abundance. Modulation of miR-153-3p resulted in seven up-regulated proteins and eight down-regulated proteins. miR-205 modulation resulted in twelve up-regulated proteins and six down-regulated proteins. Several of the proteins are associated with neuronal processes, including peroxiredoxin-2 and -4, cofilin-1, prefoldin 2, alpha-enolase, human nucleoside diphosphate kinase B (Nm23) and 14-3-3 protein epsilon. Many of the differentially expressed proteins are involved in diverse pathways including metabolism, neurotrophin signaling, actin cytoskeletal regulation, HIF-1 signaling and the proteasome indicating that miR-153-3p and miR-205-5p are involved in the regulation of a wide variety of biological processes in neuroblastoma cells.