The Parkinsonian Spectrum: Dissecting Convergent Mechanisms

The etiology of the progressive neurodegeneration that characterizes Parkinson’s disease (PD) remains relatively enigmatic, despite immense advances in our understanding of the condition. Pivotal elements that underpin current viewpoints include vital contributions from both molecular genetics and also from greatly improved understanding of the nature of aggregated proteins, which carry the potential to propagate throughout the nervous system.However, the impact of canonical Mendelian genetics in accounting for sporadic Parkinsonism appears to be considerably lower than initially hoped. The determination of the commonest variants in PD as largely being risk variants, notably as seen with GBA and LRRK2, complicates efforts to characterise the genetic underpinnings of PD. As with PD itself, age appears to be the greatest determinant of whether carriers of these variants go on to develop disease, and it is equally central to interpreting the cumulative contribution of the low-effect-size risk variants identified through genome-wide association studies.These difficulties are frequently mirrored by varied neuropathological findings, which range from being remarkably uniform in many sporadic cases, to widely diverse findings in others. Similarly, with respect to pathological characterisation of well-defined genetic causes of PD, variable findings are characteristic of LRRK2 and pathogenic variants affecting mitochondrial function (PRKN/PINK1).Although the wide range of neuronal pathology in the nervous system has been known for decades, the complexities of co-pathology, particularly of synuclein, tau, and amyloid-beta, are prominent indicators of our difficulties in understanding the basic mechanisms of disease in PD. Fundamentally, a major difficulty arises from an overall framework wherein the condition of PD is operationally defined as being levodopa responsive, coupled with clinical features of dopamine deficiency. Consequently, a gold standard for determining whether PD is present may well continue to be elusive. This Research Topic aims to review the convergent mechanisms underlying Parkinson’s disease by linking molecular insights to clinical and population-level perspectives. It seeks to identify unifying biological pathways that bridge genetic and sporadic forms of PD, as well as to explore differences across populations to highlight novel risk factors and pathogenic mechanisms. Central goals include understanding shared neurodegenerative mechanisms across disorders and identifying genetic variants relevant to diverse ethnic groups. A further aim is to clarify how molecular dysfunctions in protein and organelle homeostasis pathways translate into network-level abnormalities and clinical phenotypes.The scope of this Research Topic encompasses studies focused on mechanistic, translational, and clinical perspectives addressing the complexity and diversity of PD and related movement disorders. The Topic welcomes integrative and comparative investigations across populations and disease subtypes.To gather further insights into the convergent mechanisms and global diversity of Parkinsonian disorders, we would appreciate articles addressing, but not limited to, the following themes:o Beyond synuclein: alternative pathogenic pathwayso Gene–environment interactions in parkinsonismo Shared mechanisms across genetic and atypical parkinsonian disorderso Broader neurodegenerative mechanisms and overlapping pathologieso Clinical movement disorders and differential diagnosis within the Parkinsonian spectrumo Biomarkers and disease stratificationo Network dysfunction and circuit-based mechanismso Precision medicine in Parkinson’s disease and related disorderso Cellular and molecular mechanisms of neurodegenerationo Lysosomal and autophagy pathwayso Translational and clinical Parkinson's researcho Synuclein biology and propagation models Topic editors: Jonathan Carr, Eman Hamid Source: https://www.frontiersin.org/research-topics/83043/the-parkinsonian-spectrum-dissecting-convergent-mechanisms