Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies

Abstract

The accumulation of misfolded alpha-synuclein (aSyn) throughout the brain, as Lewy pathology, is a phenomenon central to Parkinson’s disease (PD) pathogenesis. The stereotypical distribution and evolution of the pathology during disease is often attributed to the cell-to-cell transmission of aSyn between interconnected brain regions. The spreading of conformationally distinct aSyn protein assemblies, commonly referred as strains, is thought to result in a variety of clinically and pathologically heterogenous diseases known as synucleinopathies. Although tremendous progress has been made in the field, the mechanisms involved in the transfer of these assemblies between interconnected neural networks and their role in driving PD progression are still unclear. Here, we present an update of the relevant discoveries supporting or challenging the prion-like spreading hypothesis. We also discuss the importance of aSyn strains in pathology progression and the various putative molecular mechanisms involved in cell-to-cell protein release. Understanding the pathways underlying aSyn propagation will contribute to determining the etiology of PD and related synucleinopathies but also assist in the development of new therapeutic strategies.

Common molecular mechanisms underlie the transfer of alpha-synuclein, Tau and huntingtin and modulate spontaneous activity in neuronal cells

“…In addition, abundant Tau-related pathology can be observed in the brains of PD and HD patients, suggesting that multiple proteins may jointly contribute to the pathophysiology of different neurodegenerative disorders (Cisbani et al, 2017, Fernandez-Nogales et al, 2014, Ornelas et al, 2020, Arima et al, 2000). Furthermore, the propagation of the pathological proteins between cells and across anatomical connected regions is consistent with the progression patterns described in different neurodegenerative diseases (Goedert et al, 2017, Bras and Outeiro, 2021, Alpaugh and Cicchetti, 2021). However, the precise molecular mechanisms underlying the spreading of pathology, and the relative contributions of each of them towards spreading, are still unclear.…”

“…Several neurodegenerative disease-related proteins appear to be transferred from cell-to-cell, contributing for the spreading of pathology and disease progression (Peng et al, 2020, Bras and Outeiro, 2021, Alpaugh and Cicchetti, 2021). However, the basic molecular mechanisms involved in the release of proteins which are, oftentimes, not typical secretory proteins, are still unclear.…”

“…Several conventional and unconventional pathways have been implicated in the cell-to-cell transfer of proteopathic seeds (Peng et al, 2020, Bras and Outeiro, 2021, Alpaugh and Cicchetti, 2021). The conventional secretory pathway requires the presence of a signal peptide sequence in the secreted protein that is then translocated to the endoplasmic-reticulum (ER), and sorted through Golgi-derived vesicles that, ultimately, fuse with the plasma membrane, thereby releasing their content/cargoes to the extracellular space (Andrews, 2000, Ponpuak et al, 2015, Zhang and Schekman, 2013, Lee et al, 2004).…”

Small Molecule Fisetin Modulates Alpha–Synuclein Aggregation

“…αsyn exists in equilibrium between the unfolded form in the cytoplasm and an alpha-helical-rich form when bound to membranes, but in disease conditions, it forms beta-sheet-rich amyloid fibrils that accumulate in the brain of patients [ 48 ]. The presence of αsyn toxic intracellular aggregates within the brain is the main hallmark of many neurodegenerative diseases (ND) called synucleinopathies.…”

Alpha-Synuclein and Lipids: The Elephant in the Room?

“…However, these data need still to be better understood [ 31 ]. Conversely, the spread of insoluble α-syn propagation from cell-to-cell is currently considered as a mechanism to explain the pathological progression of disease along synaptically connected regions of the brain [ 32 , 33 ]. Furthermore, many studies in post-mortem brains, indicate that the degree of microglial activation in PD is directly correlated with α-syn deposition, suggesting that α-syn may be directly involved in activating the innate immune system [ 4 ].…”