The Prion-Like Spreading of Alpha-Synuclein in Parkinson’s Disease: Update on Models and Hypotheses

The pathological aggregation of the presynaptic protein α-synuclein (α-syn) and propagation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson’s disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological α-syn accumulation in the CNS are not fully understood, growing evidence suggests that de novo α-syn misfolding and/or neuronal internalization of aggregated α-syn facilitates conformational templating of endogenous α-syn monomers in a mechanism reminiscent of prions. A refined understanding of the biochemical and cellular factors mediating the pathological neuron-to-neuron propagation of misfolded α-syn will potentially elucidate the etiology of PD and unravel novel targets for therapeutic intervention. Here, we discuss recent developments on the hypothesis regarding trans-synaptic propagation of α-syn pathology in the context of neuronal vulnerability and highlight the potential utility of novel experimental models of synucleinopathies.

Download Full-text

Parkinson’s Disease-Related Genes and Lipid Alteration

International Journal of Molecular Sciences ◽

10.3390/ijms22147630 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7630

Author(s):

Milena Fais ◽

Antonio Dore ◽

Manuela Galioto ◽

Grazia Galleri ◽

Claudia Crosio ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Clinical Manifestations ◽

Alpha Synuclein ◽

Experimental Models ◽

Protein Clearance ◽

Genetic And Environmental Factors

Parkinson’s disease (PD) is a complex and progressive neurodegenerative disorder with a prevalence of approximately 0.5–1% among those aged 65–70 years. Although most of its clinical manifestations are due to a loss of dopaminergic neurons, the PD etiology is largely unknown. PD is caused by a combination of genetic and environmental factors, and the exact interplay between genes and the environment is still debated. Several biological processes have been implicated in PD, including mitochondrial or lysosomal dysfunctions, alteration in protein clearance, and neuroinflammation, but a common molecular mechanism connecting the different cellular alterations remains incompletely understood. Accumulating evidence underlines a significant role of lipids in the pathological pathways leading to PD. Beside the well-described lipid alteration in idiopathic PD, this review summarizes the several lipid alterations observed in experimental models expressing PD-related genes and suggests a possible scenario in relationship to the molecular mechanisms of neuronal toxicity. PD could be considered a lipid-induced proteinopathy, where alteration in lipid composition or metabolism could induce protein alteration—for instance, alpha-synuclein accumulation—and finally neuronal death.

Download Full-text

Cytotoxicity and Mitochondrial Dysregulation Caused by α-Synuclein in Dictyostelium discoideum

Cells ◽

10.3390/cells9102289 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2289 ◽

Cited By ~ 1

Author(s):

Sanjanie Fernando ◽

Claire Y. Allan ◽

Katelyn Mroczek ◽

Xavier Pearce ◽

Oana Sanislav ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dictyostelium Discoideum ◽

Mitochondrial Function ◽

Molecular Mechanisms ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Cell Cortex ◽

Mutant Proteins ◽

C Terminus

Alpha synuclein has been linked to both sporadic and familial forms of Parkinson’s disease (PD) and is the most abundant protein in Lewy bodies a hallmark of Parkinson’s disease. The function of this protein and the molecular mechanisms underlying its toxicity are still unclear, but many studies have suggested that the mechanism of α-synuclein toxicity involves alterations to mitochondrial function. Here we expressed human α-synuclein and two PD-causing α-synuclein mutant proteins (with a point mutation, A53T, and a C-terminal 20 amino acid truncation) in the eukaryotic model Dictyostelium discoideum. Mitochondrial disease has been well studied in D. discoideum and, unlike in mammals, mitochondrial dysfunction results in a clear set of defective phenotypes. These defective phenotypes are caused by the chronic hyperactivation of the cellular energy sensor, AMP-activated protein kinase (AMPK). Expression of α-synuclein wild type and mutant forms was toxic to the cells and mitochondrial function was dysregulated. Some but not all of the defective phenotypes could be rescued by down regulation of AMPK revealing both AMPK-dependent and -independent mechanisms. Importantly, we also show that the C-terminus of α-synuclein is required and sufficient for the localisation of the protein to the cell cortex in D. discoideum.

Download Full-text

The molecular mechanisms underlying alpha-synuclein-evoked cell death; possible implications for the pathogenesis of Parkinson’s disease

Pharmacological Reports ◽

10.1016/s1734-1140(11)70650-8 ◽

2011 ◽

Vol 63 (5) ◽

pp. 1269

Author(s):

Agata Adamczyk ◽

Anna Kaźmierczak ◽

Grzegorz A. Czapski ◽

Joanna B. Strosznajder

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Molecular Mechanisms ◽

Alpha Synuclein

Download Full-text

DOPAL initiates αSynuclein-mediated impaired proteostasis in neuronal projections leading to enhanced vulnerability in Parkinson's disease.

10.1101/2021.06.15.448476 ◽

2021 ◽

Author(s):

Anna Masato ◽

Nicoletta Plotegher ◽

Andrea Thor ◽

Stephen Adams ◽

Michele Sandre ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Protein Quality ◽

Motor Impairment ◽

Experimental Models ◽

Early Event ◽

In Vivo Models ◽

Nigrostriatal Neuron ◽

Presynaptic Protein

Dopamine dyshomeostasis has been acknowledged to be among the determinants of nigrostriatal neuron degeneration in Parkinson's disease (PD). Several studies in experimental models and postmortem PD patients underlined increasing levels of the aldehydic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is highly reactive towards proteins. DOPAL has been shown to covalently modify the presynaptic protein αSynuclein (αSyn), whose misfolding and aggregation represent a major trait of PD pathology, triggering αSyn oligomerization in dopaminergic neurons. Here, we demonstrated that DOPAL elicits αSyn neuronal accumulation and hampers αSyn clearance at synapses and the soma. By combining cellular and in vivo models, we provided evidence that DOPAL-induced αSyn buildup lessens neuronal resilience, compromises synaptic integrity, and overwhelms protein quality control pathways, specifically at neuronal projections. The resulting progressive decline of neuronal homeostasis leads to dopaminergic neuron loss and motor impairment, corroborating the αSyn-DOPAL interplay as an early event in PD neurodegeneration.

Download Full-text

GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22042215 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2215

Author(s):

Silvia Cerri ◽

Cristina Ghezzi ◽

Gerardo Ongari ◽

Stefania Croce ◽

Micol Avenali ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Extracellular Vesicles ◽

Molecular Mechanisms ◽

Fibroblast Cell ◽

Alpha Synuclein ◽

Gene Encoding ◽

Gba Gene ◽

The Impact ◽

Gba Mutations

Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are the strongest known genetic risk factor for Parkinson’s disease (PD). The molecular mechanisms underlying the increased PD risk and the variable phenotypes observed in carriers of different GBA mutations are not yet fully elucidated. Extracellular vesicles (EVs) have gained increasing importance in neurodegenerative diseases since they can vehiculate pathological molecules potentially promoting disease propagation. Accumulating evidence showed that perturbations of the endosomal–lysosomal pathway can affect EV release and composition. Here, we investigate the impact of GCase deficiency on EV release and their effect in recipient cells. EVs were purified by ultracentrifugation from the supernatant of fibroblast cell lines derived from PD patients with or without GBA mutations and quantified by nanoparticle tracking analysis. SH-SY5Y cells over-expressing alpha-synuclein (α-syn) were used to assess the ability of patient-derived small EVs to affect α-syn expression. We observed that defective GCase activity promotes the release of EVs, independently of mutation severity. Moreover, small EVs released from PD fibroblasts carrying severe mutations increased the intra-cellular levels of phosphorylated α-syn. In summary, our work shows that the dysregulation of small EV trafficking and alpha-synuclein mishandling may play a role in GBA-associated PD.

Download Full-text

Alpha-Synuclein: The Interplay of Pathology, Neuroinflammation, and Environmental Factors in Parkinson’s Disease

Neurodegenerative Diseases ◽

10.1159/000511083 ◽

2020 ◽

Vol 20 (2-3) ◽

pp. 55-64

Author(s):

Songzhe He ◽

Shan Zhong ◽

Gang Liu ◽

Jun Yang

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Environmental Factors ◽

Dopaminergic Neurons ◽

Molecular Mechanisms ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Future Directions ◽

Main Protein ◽

Cumulative Evidence

Background: Parkinson’s disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disease. α-Synuclein (α-syn), which is the main protein component of Lewy bodies, plays an important role in the pathological hallmarks of PD. However, the pathological function of α-syn and the molecular mechanisms responsible for the degeneration of dopaminergic neurons are still elusive. Summary: Cumulative evidence implicates that abnormal processing of α-syn will be predicted to lead to pathological changes in PD. Key Messages: In this review, we summarize the structure and physiological function of α-syn, and further discuss the interplay of pathology, neuroinflammation, and environmental factors in PD. Additionally, we suggest future directions for understanding the toxicity of α-syn to neurons, which may ultimately encourage us to better design disease-modifying therapeutic strategies for PD.

Download Full-text

Alpha-synuclein levels modulate seeding and aggregation in cultured cells

10.21203/rs.3.rs-666210/v1 ◽

2021 ◽

Author(s):

Eftychia Vasili ◽

Antonio Dominguez-Meijide ◽

Manuel Flores-León ◽

Mohammed Al-Azzani ◽

Angeliki Kanellidi ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Lines ◽

Molecular Mechanisms ◽

Cultured Cells ◽

Neurodegenerative Disorder ◽

Alpha Synuclein ◽

Lewy Neurites ◽

Stable Cell Lines ◽

The Impact

Abstract Background Parkinson's disease is a progressive neurodegenerative disorder characterized by the accumulation of misfolded alpha-synuclein in intraneuronal inclusions known as Lewy bodies and Lewy neurites. Multiple studies strongly implicate the levels of alpha-synuclein as a major risk factor for the onset and progression of Parkinson’s disease. alpha-Synuclein pathology spreads progressively throughout interconnected brain regions but the precise molecular mechanisms underlying alpha-synuclein spreading and accumulation remain obscure. Methods Here, using stable cell lines expressing alpha-synuclein, we examined the correlation between endogenous alpha-synuclein levels and the seeding propensity by exogenous alpha-synuclein pre-formed fibrils. We applied biochemical approaches and imaging methods in stable cell lines expressing alpha-synuclein and in primary neurons to determine the impact of alpha-synuclein expression levels on seeding and aggregation. Results Our results indicate that alpha-synuclein levels define the pattern and severity of aggregation and the extent of p-alpha-synuclein deposition, likely explaining the selective vulnerability of different cell types in synucleinopathies. Conclusions The elucidation of the cellular processes involved in the pathological aggregation of alpha-synuclein will enable the identification of novel targets and the development of therapeutic strategies for Parkinson's disease and other synucleinopathies.

Download Full-text

High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01282-8 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Marco J. Russo ◽

Christina D. Orru ◽

Luis Concha-Marambio ◽

Simone Giaisi ◽

Bradley R. Groveman ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Clinical Diagnosis ◽

Diagnostic Performance ◽

De Novo ◽

Alpha Synuclein ◽

Diagnostic Tools ◽

Dat Spect ◽

Progression Markers ◽

Early Parkinson’S Disease

AbstractAlpha-synuclein seed amplification assays (αSyn-SAAs) are promising diagnostic tools for Parkinson’s disease (PD) and related synucleinopathies. They enable detection of seeding-competent alpha-synuclein aggregates in living patients and have shown high diagnostic accuracy in several PD and other synucleinopathy patient cohorts. However, there has been confusion about αSyn-SAAs for their methodology, nomenclature, and relative accuracies when performed by various laboratories. We compared αSyn-SAA results obtained from three independent laboratories to evaluate reproducibility across methodological variations. We utilized the Parkinson’s Progression Markers Initiative (PPMI) cohort, with DATSCAN data available for comparison, since clinical diagnosis of early de novo PD is critical for neuroprotective trials, which often use dopamine transporter imaging to enrich their cohorts. Blinded cerebrospinal fluid (CSF) samples for a randomly selected subset of PPMI subjects (30 PD, 30 HC, and 20 SWEDD), from both baseline and year 3 collections for the PD and HC groups (140 total CSF samples) were analyzed in parallel by each lab according to their own established and optimized αSyn-SAA protocols. The αSyn-SAA results were remarkably similar across laboratories, displaying high diagnostic performance (sensitivity ranging from 86 to 96% and specificity from 93 to 100%). The assays were also concordant for samples with results that differed from clinical diagnosis, including 2 PD patients determined to be clinically inconsistent with PD at later time points. All three assays also detected 2 SWEDD subjects as αSyn-SAA positive who later developed PD with abnormal DAT-SPECT. These multi-laboratory results confirm the reproducibility and value of αSyn-SAA as diagnostic tools, illustrate reproducibility of the assay in expert hands, and suggest that αSyn-SAA has potential to provide earlier diagnosis with comparable or superior accuracy to existing methods.

Download Full-text