Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid.

α-, ß-, and γ-Synuclein are intrinsically disordered proteins implicated in physiological processes in the nervous system of vertebrates. α-synuclein (αSyn) is the amyloidogenic protein associated with Parkinson's disease and certain other neurodegenerative disorders. Intensive research has focused on the mechanisms that cause αSyn to form amyloid structures, identifying its NAC region as being necessary and sufficient for amyloid assembly. Recent work has shown that a 7-residue sequence (P1) is necessary for αSyn amyloid formation. Although γ-synuclein (γSyn) is 55% identical in sequence to αSyn and its pathological deposits are also observed in association with neurodegenerative conditions, γSyn is resilient to amyloid formation in vitro. Here, we report a rare single nucleotide polymorphism (SNP) in the SNCG gene encoding γSyn, found in two patients with amyotrophic lateral sclerosis (ALS). The SNP results in the substitution of Met38 with Ile in the P1 region of the protein. These individuals also had a second, common and nonpathological, SNP in SNCG resulting in the substitution of Glu110 with Val. In vitro studies demonstrate that the Ile38 variant accelerates amyloid fibril assembly. Contrastingly, Val110 retards fibril assembly and mitigates the effect of Ile38. Substitution of residue 38 with Leu had little effect, while Val retards, and Ala increases the rate of amyloid formation. Ile38 γSyn also results in the formation of γSyn-containing inclusions in cells. The results show how a single point substitution can enhance amyloid formation of γSyn and highlight the P1 region in driving amyloid formation in another synuclein family member.

Targeting Biomolecular Condensation and Protein Aggregation against Cancer.

Biomolecular condensates, membrane-less entities arising from liquid-liquid phase separation, hold dichotomous roles in health and disease. Alongside their physiological functions, these condensates can transition to a solid phase, producing amyloid-like structures implicated in degenerative diseases and cancer. This review thoroughly examines the dual nature of biomolecular condensates, spotlighting their role in cancer, particularly concerning the p53 tumor suppressor. Given that over half of the malignant tumors possess mutations in the TP53 gene, this topic carries profound implications for future cancer treatment strategies. Notably, p53 not only misfolds but also forms biomolecular condensates and aggregates analogous to other protein-based amyloids, thus significantly influencing cancer progression through loss-of-function, negative dominance, and gain-of-function pathways. The exact molecular mechanisms underpinning the gain-of-function in mutant p53 remain elusive. However, cofactors like nucleic acids and glycosaminoglycans are known to be critical players in this intersection between diseases. Importantly, we reveal that molecules capable of inhibiting mutant p53 aggregation can curtail tumor proliferation and migration. Hence, targeting phase transitions to solid-like amorphous and amyloid-like states of mutant p53 offers a promising direction for innovative cancer diagnostics and therapeutics.

Aggregation and beyond: alpha-synuclein-based biomarkers in synucleinopathies.

Parkinson's disease is clinically known for the loss of dopaminergic neurons in the substantia nigra pars compacta and accumulation of intraneuronal cytoplasmic inclusions rich in alpha-synuclein called 'Lewy bodies' and 'Lewy neurites'. Together with dementia with Lewy bodies and multiple system atrophy, Parkinson's disease is part of a group of disorders called synucleinopathies. Currently, diagnosis of synucleinopathies is based on the clinical assessment which often takes place in advanced disease stages. While the causal role of alpha-synuclein aggregates in these disorders is still debatable, measuring the levels, types or seeding properties of different alpha-synuclein species hold great promise as biomarkers. Recent studies indicate significant differences in peptide, protein and RNA levels in blood samples from patients with Parkinson's disease. Seed amplification assays using CSF, blood, skin biopsy, olfactory swab samples show great promise for detecting synucleinopathies and even for discriminating between different synucleinopathies. Interestingly, small extracellular vesicles, such as exosomes, display differences in their cargoes in Parkinson's disease patients versus controls. In this update, we focus on alpha-synuclein aggregation and possible sources of disease-related species released in extracellular vesicles, which promise to revolutionize the diagnosis and the monitoring of disease progression.

The lysosomal ß-glucocerebrosidase strikes mitochondria: implications for Parkinson's therapeutics.

Parkinson's disease (PD) is a neurodegenerative disorder primarily known for typical motor features that arise due to the loss of dopaminergic neurons in the substantia nigra. However, the precise molecular etiology of the disease is still unclear. Several cellular pathways have been linked to PD, including the autophagy-lysosome pathway (ALP), α-synuclein (α-syn) aggregation, and mitochondrial function. Interestingly, the mechanistic link between GBA1, the gene that encodes for lysosomal ß-glucocerebrosidase (GCase), and PD lies in the interplay between GCase functions in the lysosome and mitochondria. GCase mutations alter mitochondria-lysosome contact sites. In the lysosome, reduced GCase activity leads to glycosphingolipid buildup, disrupting lysosomal function and autophagy, thereby triggering α-syn accumulation. Additionally, α-syn aggregates reduce GCase activity, creating a self-perpetuating cycle of lysosomal dysfunction and α-syn accumulation. GCase can also be imported into the mitochondria, where it promotes the integrity and function of mitochondrial complex I. Thus, GCase mutations that impair its normal function increase oxidative stress in mitochondria, the compartment where dopamine is oxidized. In turn, the accumulation of oxidized dopamine-adducts further impairs GCase activity, creating a second cycle of GCase dysfunction. The oxidative state triggered by GCase dysfunction can also induce mitochondrial DNA damage which, in turn, can cause dopaminergic cell death. In this review, we highlight the pivotal role of GCase in PD pathogenesis and discuss promising examples of GCase-based therapeutics such as gene and enzyme replacement therapies, small molecule chaperones, and substrate reduction therapies, among others, as potential therapeutic interventions.

α-Synuclein phosphorylation at serine 129 occurs after initial protein deposition and inhibits seeded fibril formation and toxicity.

α-Synuclein (α-syn) phosphorylation at serine 129 (pS129­α-syn) is substantially increased in Lewy body disease, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the pathogenic relevance of pS129­α-syn remains controversial, so we sought to identify when pS129 modification occurs during α-syn aggregation and its role in initiation, progression and cellular toxicity of disease. Using diverse aggregation assays, including real-time quaking-induced conversion (RT-QuIC) on brain homogenates from PD and DLB cases, we demonstrated that pS129­α-syn inhibits α-syn fibril formation and seeded aggregation. We also identified lower seeding propensity of pS129­α-syn in cultured cells and correspondingly attenuated cellular toxicity. To build upon these findings, we developed a monoclonal antibody (4B1) specifically recognizing nonphosphorylated S129­α-syn (WT­α-syn) and noted that S129 residue is more efficiently phosphorylated when the protein is aggregated. Using this antibody, we characterized the time-course of α-syn phosphorylation in organotypic mouse hippocampal cultures and mice injected with α-syn preformed fibrils, and we observed aggregation of nonphosphorylated α-syn followed by later pS129­α-syn. Furthermore, in postmortem brain tissue from PD and DLB patients, we observed an inverse relationship between relative abundance of nonphosphorylated α-syn and disease duration. These findings suggest that pS129­α-syn occurs subsequent to initial protein aggregation and apparently inhibits further aggregation. This could possibly imply a potential protective role for pS129­α-syn, which has major implications for understanding the pathobiology of Lewy body disease and the continued use of reduced pS129­α-syn as a measure of efficacy in clinical trials.

In silico analysis of alpha-synuclein protein variants and posttranslational modifications related to Parkinson's disease.

Parkinson's disease (PD) is among the most prevalent neurodegenerative disorders, affecting over 10 million people worldwide. The protein encoded by the SNCA gene, alpha-synuclein (ASYN), is the major component of Lewy body (LB) aggregates, a histopathological hallmark of PD. Mutations and posttranslational modifications (PTMs) in ASYN are known to influence protein aggregation and LB formation, possibly playing a crucial role in PD pathogenesis. In this work, we applied computational methods to characterize the effects of missense mutations and PTMs on the structure and function of ASYN. Missense mutations in ASYN were compiled from the literature/databases and underwent a comprehensive predictive analysis. Phosphorylation and SUMOylation sites of ASYN were retrieved from databases and predicted by algorithms. ConSurf was used to estimate the evolutionary conservation of ASYN amino acids. Molecular dynamics (MD) simulations of ASYN wild-type and variants A30G, A30P, A53T, and G51D were performed using the GROMACS package. Seventy-seven missense mutations in ASYN were compiled. Although most mutations were not predicted to affect ASYN stability, aggregation propensity, amyloid formation, and chaperone binding, the analyzed mutations received relatively high rates of deleterious predictions and predominantly occurred at evolutionarily conserved sites within the protein. Moreover, our predictive analyses suggested that the following mutations may be possibly harmful to ASYN and, consequently, potential targets for future investigation: K6N, T22I, K34E, G36R, G36S, V37F, L38P, G41D, and K102E. The MD analyses pointed to remarkable flexibility and essential dynamics alterations at nearly all domains of the studied variants, which could lead to impaired contact between NAC and the C-terminal domain triggering protein aggregation. These alterations may have functional implications for ASYN and provide important insight into the molecular mechanism of PD, supporting the design of future biomedical research and improvements in existing therapies for the disease.

Aging and neurodegeneration: From molecular mechanisms to therapeutic interventions.

Protein aggregation is a common age-associated process and can be a pathological hallmark of various neurodegenerative conditions, possibly because of an age-associated decline in the activity of components of the proteostasis network. The specific molecular drivers of protein aggregation in certain cell types are not well understood, posing tremendous challenges to current research aimed at devising strategies to treat neurodegenerative diseases. This preface introduces the special issue "Aging and Neurodegeneration: from molecular mechanisms to therapeutic interventions," featuring articles that assess the drivers of pathology in the aging cell, including oxidative stress, protein glycation/aggregation, and mitochondrial impairment.

Altered hippocampal doublecortin expression in Parkinson's disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by motor and non-motor symptoms. Motor symptoms include bradykinesia, resting tremors, muscular rigidity, and postural instability, while non-motor symptoms include cognitive impairments, mood disturbances, sleep disturbances, autonomic dysfunction, and sensory abnormalities. Some of these symptoms may be influenced by the proper hippocampus functioning, including adult neurogenesis. Doublecortin (DCX) is a microtubule-associated protein that plays a pivotal role in the development and differentiation of migrating neurons. This study utilized postmortem human brain tissue of PD and age-matched control individuals to investigate DCX expression in the context of adult hippocampal neurogenesis. Our findings demonstrate a significant reduction in the number of DCX-expressing cells within the subgranular zone (SGZ), as well as a decrease in the nuclear area of these DCX-positive cells in postmortem brain tissue obtained from PD cases, suggesting an impairment in the adult hippocampal neurogenesis. Additionally, we found that the nuclear area of DCX-positive cells correlates with pH levels. In summary, we provide evidence supporting that the process of hippocampal adult neurogenesis is likely to be compromised in PD patients before cognitive dysfunction, shedding light on potential mechanisms contributing to the neuropsychiatric symptoms observed in affected individuals. Understanding these mechanisms may offer novel insights into the pathophysiology of PD and possible therapeutic avenues.

Alpha-synuclein overexpression induces epigenomic dysregulation of glutamate signaling and locomotor pathways.

Parkinson's disease (PD) is a neurological disorder with complex interindividual etiology that is becoming increasingly prevalent worldwide. Elevated alpha-synuclein levels can increase risk of PD and may influence epigenetic regulation of PD pathways. Here, we report genome-wide DNA methylation and hydroxymethylation alterations associated with overexpression of two PD-linked alpha-synuclein variants (wild-type and A30P) in LUHMES cells differentiated to dopaminergic neurons. Alpha-synuclein altered DNA methylation at thousands of CpGs and DNA hydroxymethylation at hundreds of CpGs in both genotypes, primarily in locomotor behavior and glutamate signaling pathway genes. In some cases, epigenetic changes were associated with transcription. SMITE network analysis incorporating H3K4me1 ChIP-seq to score DNA methylation and hydroxymethylation changes across promoters, enhancers, and gene bodies confirmed epigenetic and transcriptional deregulation of glutamate signaling modules in both genotypes. Our results identify distinct and shared impacts of alpha-synuclein variants on the epigenome, and associate alpha-synuclein with the epigenetic etiology of PD.

Synthesis and Semi-Synthesis of Alpha-Synuclein: Insight into the Chemical Complexity of Synucleinopathies.

The chemical rules governing protein folding have intrigued generations of researchers for decades. With the advent of artificial intelligence (AI), prediction of protein structure has improved tremendously. However, there is still a level of analysis that is only possible through wet laboratory experiments, especially in respect to the investigation of the pathological effect of mutations and posttranslational modifications (PTMs) on proteins of interest. This requires the availability of pure peptides and proteins in sufficient quantities for biophysical, biochemical, and functional studies. In this context, chemical protein synthesis and semi-synthesis are powerful tools in protein research, which help to enlighten the role of protein modification in the physiology and pathology of proteins. A protein of high interest in the field of biomedicine is alpha-synuclein (aSyn), a protein deeply associated with several devastating neurodegenerative disorders such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), or multiple systems atrophy (MSA). Here, we describe several methods and pathways to synthesize native or modified aSyn, and discuss how these approaches enable us to address pathological mechanisms that may open novel perspectives for therapeutic intervention.

Regional AT-8 reactive tau species correlate with intracellular Aß levels in cases of low AD neuropathologic change.

The amyloid cascade hypothesis states that Aß aggregates induce pathological changes in tau, leading to neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the spatio-temporal divide between plaques and NFTs. This has been addressed by the inclusion of soluble Aß and tau species in the revised amyloid cascade hypothesis. Nevertheless, despite the potential for non-plaque Aß to contribute to tau pathology, few studies have examined relative correlative strengths between total Aß, plaque Aß and intracellular Aß with tau pathology within a single tissue cohort. Employing frozen and fixed frontal cortex grey and white matter tissue from non-AD controls (Con; n = 39) and Alzheimer's disease (AD) cases (n = 21), biochemical and immunohistochemical (IHC) measures of Aß and AT-8 phosphorylated tau were assessed. Biochemical native-state dot blots from crude tissue lysates demonstrated robust correlations between total Aß and AT-8 tau, when considered as a combined cohort (Con and AD) and when as Con and AD cases, separately. In contrast, no associations between Aß plaques and AT-8 were reported when using IHC measurements in either Con or AD cases. However, when intracellular Aß was measured via the Aß specific antibody MOAB-2, a correlative relationship with AT-8 tau was reported in non-AD controls but not in AD cases. Collectively the data suggests that accumulating intracellular Aß may influence AT-8 pathology, early in AD-related neuropathological change. Despite the lower levels of phospho-tau and Aß in controls, the robust correlative relationships observed suggest a physiological association of Aß production and tau phosphorylation, which may be modified during disease. This study is supportive of a revised amyloid cascade hypothesis and demonstrates regional associative relationships between tau pathology and intracellular Aß, but not extracellular Aß plaques.

Research Priorities on the Role of α-Synuclein in Parkinson's Disease Pathogenesis.

Various forms of Parkinson's disease, including its common sporadic form, are characterized by prominent α-synuclein (αSyn) aggregation in affected brain regions. However, the role of αSyn in the pathogenesis and evolution of the disease remains unclear, despite vast research efforts of more than a quarter century. A better understanding of the role of αSyn, either primary or secondary, is critical for developing disease-modifying therapies. Previous attempts to hone this research have been challenged by experimental limitations, but recent technological advances may facilitate progress. The Scientific Issues Committee of the International Parkinson and Movement Disorder Society (MDS) charged a panel of experts in the field to discuss current scientific priorities and identify research strategies with potential for a breakthrough. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Basic Science in Movement Disorders: Fueling the Engine of Translation into Clinical Practice.

Basic Science is crucial for the advancement of clinical care for Movement Disorders. Here, we provide brief updates on how basic science is important for understanding disease mechanisms, disease prevention, disease diagnosis, development of novel therapies and to establish the basis for personalized medicine. We conclude the viewpoint by a call to action to further improve interactions between clinician and basic scientists. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Physical Exercise-Induced Activation of NRF2 and BDNF as a Promising Strategy for Ferroptosis Regulation in Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Ferroptosis, an iron-dependent form of regulated cell death, may contribute to the progression of PD owing to an unbalanced brain redox status. Physical exercise is a complementary therapy that can modulate ferroptosis in PD by regulating the redox system through the activation of nuclear factor (erythroid-derived 2)-like 2 (NRF2) and brain-derived neurotrophic factor (BDNF) signaling. However, the precise effects of physical exercise on ferroptosis in PD remain unclear. In this review, we explored how physical exercise influences NRF2 and BDNF signaling and affects ferroptosis in PD. We further investigated relevant publications over the past two decades by searching the PubMed, Web of Science, and Google Scholar databases using keywords related to physical exercise, PD, ferroptosis, and neurotrophic factor antioxidant signaling. This review provides insights into current research gaps and demonstrates the necessity for future research to elucidate the specific mechanisms by which exercise regulates ferroptosis in PD, including the assessment of different exercise protocols and their long-term effects. Ultimately, exploring these aspects may lead to the development of improved exercise interventions for the better management of patients with PD.

Chemical synthesis of site-selective advanced glycation end products in α-synuclein and its fragments.

Advanced glycation end products (AGEs) arise from the Maillard reaction between dicarbonyls and proteins, nucleic acids, or specific lipids. Notably, AGEs are linked to aging and implicated in various disorders, spanning from cancer to neurodegenerative diseases. While dicarbonyls like methylglyoxal preferentially target arginine residues, lysine-derived AGEs, such as N(6)-(1-carboxymethyl)lysine (CML) and N(6)-(1-carboxyethyl)lysine (CEL), are also abundant. Predicting protein glycation in vivo proves challenging due to the intricate nature of glycation reactions. In vitro, glycation is difficult to control, especially in proteins that harbor multiple glycation-prone amino acids. α-Synuclein (aSyn), pivotal in Parkinson's disease and synucleinopathies, has 15 lysine residues and is known to become glycated at multiple lysine sites. To understand the influence of glycation in specific regions of aSyn on its behavior, a strategy for site-specific glycated protein production is imperative. To fulfill this demand, we devised a synthetic route integrating solid-phase peptide synthesis, orthogonal protection of amino acid side-chain functionalities, and reductive amination strategies. This methodology yielded two disease-related N-terminal peptide fragments, each featuring five and six CML and CEL modifications, alongside a full-length aSyn protein containing a site-selective E46CEL modification. Our synthetic approach facilitates the broad introduction of glycation motifs at specific sites, providing a foundation for generating glycated forms of synucleinopathy-related and other disease-relevant proteins.

DEAD-box RNA helicase Dbp4/DDX10 is an enhancer of α-synuclein toxicity and oligomerization.

Parkinson's disease is a neurodegenerative disorder associated with misfolding and aggregation of α-synuclein as a hallmark protein. Two yeast strain collections comprising conditional alleles of essential genes were screened for the ability of each allele to reduce or improve yeast growth upon α-synuclein expression. The resulting 98 novel modulators of α-synuclein toxicity clustered in several major categories including transcription, rRNA processing and ribosome biogenesis, RNA metabolism and protein degradation. Furthermore, expression of α-synuclein caused alterations in pre-rRNA transcript levels in yeast and in human cells. We identified the nucleolar DEAD-box helicase Dbp4 as a prominent modulator of α-synuclein toxicity. Downregulation of DBP4 rescued cells from α-synuclein toxicity, whereas overexpression led to a synthetic lethal phenotype. We discovered that α-synuclein interacts with Dbp4 or its human ortholog DDX10, sequesters the protein outside the nucleolus in yeast and in human cells, and stabilizes a fraction of α-synuclein oligomeric species. These findings provide a novel link between nucleolar processes and α-synuclein mediated toxicity with DDX10 emerging as a promising drug target.

Glycation modulates alpha-synuclein fibrillization kinetics: A sweet spot for inhibition.

Glycation is a nonenzymatic posttranslational modification (PTM) known to be increased in the brains of hyperglycemic patients. Alpha-synuclein (αSN), a central player in the etiology of Parkinson's disease, can be glycated at lysine residues, thereby reducing αSN fibril formation in vitro and modulating αSN aggregation in cells. However, the molecular basis for these effects is unclear. To elucidate this, we investigated the aggregation of αSN modified by eight glycating agents, namely the dicarbonyl compound methylglyoxal (MGO) and the sugars ribose, fructose, mannose, glucose, galactose, sucrose, and lactose. We found that MGO and ribose modify αSN to the greatest extent, and these glycation products are the most efficient inhibitors of fibril formation. We show glycation primarily inhibits elongation rather than nucleation of αSN and has only a modest effect on the level of oligomerization. Furthermore, glycated αSN is not significantly incorporated into fibrils. For both MGO and ribose, we discovered that a level of ∼5 modifications per αSN is optimal for inhibition of elongation. The remaining sugars showed a weak but optimal inhibition at ∼2 modifications per αSN. We propose that this optimal level balances the affinity for the growing ends of the fibril (which decreases with the extent of modification) with the ability to block incorporation of subsequent αSN subunits (which increases with modification). Our results are not only relevant for other αSN PTMs but also for understanding PTMs affecting other fibrillogenic proteins and may thus open novel avenues for therapeutic intervention in protein aggregation disorders.

The small aromatic compound SynuClean-D inhibits the aggregation and seeded polymerization of multiple α-synuclein strains.

Parkinson's disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, as well as the accumulation of intraneuronal proteinaceous inclusions known as Lewy bodies and Lewy neurites. The major protein component of Lewy inclusions is the intrinsically disordered protein α-synuclein (α-Syn), which can adopt diverse amyloid structures. Different conformational strains of α-Syn have been proposed to be related to the onset of distinct synucleinopathies; however, how specific amyloid fibrils cause distinctive pathological traits is not clear. Here, we generated three different α-Syn amyloid conformations at different pH and salt concentrations and analyzed the activity of SynuClean-D (SC-D), a small aromatic molecule, on these strains. We show that incubation of α-Syn with SC-D reduced the formation of aggregates and the seeded polymerization of α-Syn in all cases. Moreover, we found that SC-D exhibited a general fibril disaggregation activity. Finally, we demonstrate that treatment with SC-D also reduced strain-specific intracellular accumulation of phosphorylated α-Syn inclusions. Taken together, we conclude that SC-D may be a promising hit compound to inhibit polymorphic α-Syn aggregation.

PrP meets alpha-synuclein: Molecular mechanisms and implications for disease.

The discovery of prions has challenged dogmas and has revolutionized our understanding of protein-misfolding diseases. The concept of self-propagation via protein conformational changes, originally discovered for the prion protein (PrP), also applies to other proteins that exhibit similar behavior, such as alpha-synuclein (aSyn), a central player in Parkinson's disease and in other synucleinopathies. aSyn pathology appears to spread from one cell to another during disease progression, and involves the misfolding and aggregation of aSyn. How the transfer of aSyn between cells occurs is still being studied, but one important hypothesis involves receptor-mediated transport. Interestingly, recent studies indicate that the cellular prion protein (PrPC ) may play a crucial role in this process. PrPC has been shown to act as a receptor/sensor for protein aggregates in different neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. Here, we provide a comprehensive overview of the current state of knowledge regarding the interaction between aSyn and PrPC and discuss its role in synucleinopathies. We examine the properties of PrP and aSyn, including their structure, function, and aggregation. Additionally, we discuss the current understanding of PrPC 's role as a receptor/sensor for aSyn aggregates and identify remaining unanswered questions in this area of research. Ultimately, we posit that exploring the interaction between aSyn and PrPC may offer potential treatment options for synucleinopathies.

Is it all the RAGE? Defining the role of the receptor for advanced glycation end products in Parkinson's disease.

The receptor for advanced glycation end products (RAGE) is a transmembrane receptor that belongs to the immunoglobulin superfamily and is extensively associated with chronic inflammation in non-transmissible diseases. As chronic inflammation is consistently present in neurodegenerative diseases, it was largely assumed that RAGE could act as a critical modulator of neuroinflammation in Parkinson's disease (PD), similar to what was reported for Alzheimer's disease (AD), where RAGE is postulated to mediate pro-inflammatory signaling in microglia by binding to amyloid-ß peptide. However, accumulating evidence from studies of RAGE in PD models suggests a less obvious scenario. Here, we review physiological aspects of RAGE and address the current questions about the potential involvement of this receptor in the cellular events that may be critical for the development and progression of PD, exploring possible mechanisms beyond the classical view of the microglial activation/neuroinflammation/neurodegeneration axis that is widely assumed to be the general mechanism of RAGE action in the adult brain.