Diagnostic and therapeutic approaches focused on α–synuclein

Abstract

Parkinson disease (PD), Multiple System Atrophy (MSA), and Lewy Body Dementia, known as synucleinopathies, share a common pathology : the accumulation of α–synuclein (α–syn) aggregates. Normally soluble, α–syn undergoes a structural transformation into β–sheet–rich aggregates that act as seeds, promoting further aggregation of the protein. Traditionally, synucleinopathies have been diagnosed through neurological exams, but recent progress in biomarkers and brain imaging has enhanced the understanding of PD's pathophysiology, moving towards a biological diagnosis. This advancement holds promise for early disease detection and monitoring progression, contingent on finding reliable biomarkers that mirror the underlying biochemical changes. A key pathological hallmark of PD is the Lewy body, predominantly made up of phosphorylated α–syn. Genetic alterations in the SNCA gene, responsible for α–syn production, have been linked to familial forms of parkinsonism, highlighting α–syn's critical role in PD. The hypothesis that misfolded α–syn can propagate between cells, akin to prions, expanding pathology, has brought attention to both intrinsic and extrinsic mechanisms of neurodegeneration. Targeting α–syn aggregation and spread is now a focal point in developing therapies for these conditions.