Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles

Abstract

Alpha-synuclein (α-syn) is localized in cellular organelles of most neurons, but many of its physiological functions are only partially understood. α-syn accumulation is associated with Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy as well as other synucleinopathies; however, the exact pathomechanisms that underlie these neurodegenerative diseases remain elusive. In this review, we describe what is known about α-syn function and pathophysiological changes in different cellular structures and organelles, including what is known about its behavior as a prion-like protein. We summarize current knowledge of α-syn and its pathological forms, covering its effect on each organelle, including aggregation and toxicity in different model systems, with special interest on the mitochondria due to its relevance during the apoptotic process of dopaminergic neurons. Moreover, we explore the effect that α-syn exerts by interacting with chromatin remodeling proteins that add or remove histone marks, up-regulate its own expression, and resume the impairment that α-syn induces in vesicular traffic by interacting with the endoplasmic reticulum. We then recapitulate the events that lead to Golgi apparatus fragmentation, caused by the presence of α-syn. Finally, we report the recent findings about the accumulation of α-syn, indirectly produced by the endolysosomal system. In conclusion, many important steps into the understanding of α-syn have been made using in vivo and in vitro models; however, the time is right to start integrating observational studies with mechanistic models of α-syn interactions, in order to look at a more complete picture of the pathophysiological processes underlying α-synucleinopathies.

Keywords: Golgi apparatus; Lewy bodies; alpha-synuclein; endoplasmic reticulum; mitochondria; nucleus; organelle; synucleinopathies.

FIGURE 1

Interaction of the alpha-synuclein with soluble proteins by STRING and BioGRID³.⁵. (A) STRING and (B) BioGRID³.⁵ show that alpha-synuclein (α-syn) interacts mostly with kinase proteins like LRKK2, MAPK1, Fyn, etc. and it can interact with ubiquitin proteins like PARK2, PARK7, STUB1, etc. Each interactor is shown as a circle and the lines represent the interaction between the proteins. The interactors in a red box are mentioned in the interaction section and also throughout the review.

FIGURE 2

Alpha-synuclein conformations and its interactions in mitochondria. (1) Alpha-synuclein (α-syn) monomers enter the mitochondria (Mit) through translocase of the outer membrane (TOM) and voltage-dependent anion channels (VDAC), but oligomers and pS129-α-syn on TOM and α-syn accumulation on VDAC can inhibit the protein import into the mitochondria, affecting the process that depends on cytosolic proteins. (2) Once inside, α-syn can interact with complex I of the electron transport chain, raising reactive oxygen species (ROS) production within the mitochondria, and favoring the aggregation of α-syn monomers into oligomers, which in turn produces more ROS, creating a cycle where α-syn aggregation and ROS production exacerbate each other. (3) The increased amount of ROS oxidizes the ATP synthase β-subunit, diminishing mitochondrial ATP levels as well as (4) damaging mitochondrial DNA (mtDNA), which may lead to an altered expression of mitochondrial genome-encoded genes. (5) α-syn monomers can also block mitochondrial fusion stalk, producing mitochondrial fragmentation. (6) In addition, α-syn induces the opening of permeability transition pore (PTP), allowing cytochrome C (cyt C) leak, depolarization, calcium diffusion, and swelling of the mitochondria, leading to cell apoptosis. (7) Certain stress events such as ROS can stimulate the translocation of cardiolipin from the inner membrane to the outer membrane, where it acts as a buffer for aggregative synuclein forms. See the text for further details. Created with BioRender.

FIGURE 3

Alpha-synuclein interactions in the nucleus, Golgi apparatus, and the endoplasmic reticulum. (1) Human wild type alpha-synuclein (hWT α-syn) can retain methyltransferases in the cytoplasm, thus altering DNA methylation of the SNCA gene. (2) hWT α-syn can also interact with H3K9me1/2 to increase mono- and dimethylation in the DNA. (3) p.A53T and p.A30P monomers bind to HDACS and inhibit histone deacetylation. (4) Decreased epigenetic regulation on the SNCA gene promotes its up-regulation, increasing α-syn transcription and further accumulation. (5) Prefibrillar α-syn can disrupt postraductional processing of dopamine transporter (DAT) in the Golgi apparatus (GA), diminishing its presence in the membrane. (6) α-syn oligomers impair autophagosome formation in the GA. (7) p.A53T monomers inhibit vesicles transport from endoplasmic reticulum (ER) to GA. (8) pS129-α-syn monomers increase unfolded protein response (UPR) activity in the ER. (9) p.A53T and p.A30P monomers increase levels of stress in the ER. (10) α-syn oligomers and fibrils affect SERCA complex in the ER, diminishing cytosolic levels of Ca²⁺. Created with BioRender.