Molecular changes in the postmortem parkinsonian brain

Abstract

Parkinson disease (PD) is the second most common neurodegenerative disease after Alzheimer disease. Although PD has a relatively narrow clinical phenotype, it has become clear that its etiological basis is broad. Post-mortem brain analysis, despite its limitations, has provided invaluable insights into relevant pathogenic pathways including mitochondrial dysfunction, oxidative stress and protein homeostasis dysregulation. Identification of the genetic causes of PD followed the discovery of these abnormalities, and reinforced the importance of the biochemical defects identified post-mortem. Recent genetic studies have highlighted the mitochondrial and lysosomal areas of cell function as particularly significant in mediating the neurodegeneration of PD. Thus the careful analysis of post-mortem PD brain biochemistry remains a crucial component of research, and one that offers considerable opportunity to pursue etiological factors either by 'reverse biochemistry' i.e. from defective pathway to mutant gene, or by the complex interplay between pathways e.g. mitochondrial turnover by lysosomes. In this review we have documented the spectrum of biochemical defects identified in PD post-mortem brain and explored their relevance to metabolic pathways involved in neurodegeneration. We have highlighted the complex interactions between these pathways and the gene mutations causing or increasing risk for PD. These pathways are becoming a focus for the development of disease modifying therapies for PD.

Protein aggregation into insoluble deposits protects from oxidative stress

“…It has been observed that mutations causing or exacerbating these proteinopathies increase, in many cases, the protein propensity to form aggregates, thus linking the formation of protein deposits in the brain and the degeneration of the nervous system [55]. Also, there are mounting evidences for a major contribution of oxidative stress in the pathology of these disorders [56], [57], with clear indications of oxidative damage to lipids, proteins and DNA in patient’s post-mortem brains [19], [24], [26], [27]. The connection between protein aggregation propensity and oxidative stress has been demonstrated in models of HD, where the aggregation tendency of the protein is determined by the length of the poly(Q) expansion, longer poly(Q) stretches being more aggregation-prone and inducing higher ROS production than shorter segments in wild type sequences [58].…”

“…Cumulative oxidative stress induces membrane damage, impairment of the DNA repair system and mitochondrial dysfunction, which ultimately can lead to cell death [24], [25]. Accordingly, there is clear evidence of oxidative damage in postmortem AD, PD and HD brains [26], [27], [28]. The mechanism by which aggregating proteins may induce oxidative stress in the brain is not completely understood, but the interaction between these two phenomena is bidirectional, in such a way that aggregation-prone conformers increase the production of reactive oxygen species (ROS), while at the same time oxidative stress exacerbates protein aggregation [28].…”

ASIC1a Deficient Mice Show Unaltered Neurodegeneration in the Subacute MPTP Model of Parkinson Disease

“…Activation of microglia and increased pro-inflammatory cytokines have been described in PD patients [1–5] and in animal models of PD [6]. Moreover, medication with anti-inflammatory drugs can reduce the risk of developing PD [7].…”

199 years of Parkinson disease – what have we learned and what is the path to the future?

“…In this issue of the Journal of Neurochemistry , Toulorge and colleagues describe in detail the molecular and biochemical changes in post‐mortem brain (Toulorge et al . ), Bose and Beal describe the latest developments in mitochondrial dysfunction (Bose and Beal ), and Belaidi and Bush () in iron neurochemistry and therapeutic approaches. Furthermore, Voigt and colleagues elaborate on mitophagy and the function of the mitochondrial kinase PINK1 (Voigt et al .…”