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Molecular Neurodegeneration Aug 2023Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene cause late-onset, autosomal dominant Parkinson's disease (PD), with a single missense mutation...
BACKGROUND
Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene cause late-onset, autosomal dominant Parkinson's disease (PD), with a single missense mutation (Asp620Asn, D620N) known to segregate with disease in families with PD. The VPS35 gene encodes a core component of the retromer complex, involved in the endosomal sorting and recycling of transmembrane cargo proteins. VPS35-linked PD is clinically indistinguishable from sporadic PD, although it is not yet known whether VPS35-PD brains exhibit α-synuclein-positive brainstem Lewy pathology that is characteristic of sporadic cases. Prior studies have suggested a functional interaction between VPS35 and the PD-linked gene product α-synuclein in lower organisms, where VPS35 deletion enhances α-synuclein-induced toxicity. In mice, VPS35 overexpression is reported to rescue hippocampal neuronal loss in human α-synuclein transgenic mice, potentially suggesting a retromer deficiency in these mice.
METHODS
Here, we employ multiple well-established genetic rodent models to explore a functional or pathological interaction between VPS35 and α-synuclein in vivo.
RESULTS
We find that endogenous α-synuclein is dispensable for nigrostriatal pathway dopaminergic neurodegeneration induced by the viral-mediated delivery of human D620N VPS35 in mice, suggesting that α-synuclein does not operate downstream of VPS35. We next evaluated retromer levels in affected brain regions from human A53T-α-synuclein transgenic mice, but find normal levels of the core subunits VPS35, VPS26 or VPS29. We further find that heterozygous VPS35 deletion fails to alter the lethal neurodegenerative phenotype of these A53T-α-synuclein transgenic mice, suggesting the absence of retromer deficiency in this PD model. Finally, we explored the neuroprotective capacity of increasing VPS35 expression in a viral-based human wild-type α-synuclein rat model of PD. However, we find that the overexpression of wild-type VPS35 is not sufficient for protection against α-synuclein-induced nigral dopaminergic neurodegeneration, α-synuclein pathology and reactive gliosis.
CONCLUSION
Collectively, our data suggest a limited interaction of VPS35 and α-synuclein in neurodegenerative models of PD, and do not provide support for their interaction within a common pathophysiological pathway.
Topics: Animals; Humans; Mice; Rats; alpha-Synuclein; Membrane Proteins; Mice, Transgenic; Parkinson Disease; Protein Transport; Rodentia; Vesicular Transport Proteins
PubMed: 37542299
DOI: 10.1186/s13024-023-00641-4 -
International Journal of Molecular... Jul 2023Emerging evidence supports that altered α-tubulin acetylation occurs in Parkinson's disease (PD), a neurodegenerative disorder characterized by the deposition of...
Emerging evidence supports that altered α-tubulin acetylation occurs in Parkinson's disease (PD), a neurodegenerative disorder characterized by the deposition of α-synuclein fibrillary aggregates within Lewy bodies and nigrostriatal neuron degeneration. Nevertheless, studies addressing the interplay between α-tubulin acetylation and α-synuclein are lacking. Here, we investigated the relationship between α-synuclein and microtubules in primary midbrain murine neurons and the substantia nigra of post-mortem human brains. Taking advantage of immunofluorescence and Proximity Ligation Assay (PLA), a method allowing us to visualize protein-protein interactions in situ, combined with confocal and super-resolution microscopy, we found that α-synuclein and acetylated α-tubulin colocalized and were in close proximity. Next, we employed an α-synuclein overexpressing cellular model and tested the role of α-tubulin acetylation in α-synuclein oligomer formation. We used the α-tubulin deacetylase HDAC6 inhibitor Tubacin to modulate α-tubulin acetylation, and we evaluated the presence of α-synuclein oligomers by PLA. We found that the increase in acetylated α-tubulin significantly induced α-synuclein oligomerization. In conclusion, we unraveled the link between acetylated α-tubulin and α-synuclein and demonstrated that α-tubulin acetylation could trigger the early step of α-synuclein aggregation. These data suggest that the proper regulation of α-tubulin acetylation might be considered a therapeutic strategy to take on PD.
Topics: Animals; Humans; Mice; alpha-Synuclein; Lewy Bodies; Microtubules; Parkinson Disease; Tubulin
PubMed: 37569662
DOI: 10.3390/ijms241512287 -
Chemical Communications (Cambridge,... Jul 2023The aberrant aggregation of α-Synuclein (αS), a disordered protein primarily localised at the neuronal synapses, is associated with a number of neurodegenerative... (Review)
Review
The aberrant aggregation of α-Synuclein (αS), a disordered protein primarily localised at the neuronal synapses, is associated with a number of neurodegenerative disorders including Parkinson's disease (PD). The biological properties of αS are strictly connected with its ability to bind synaptic membranes under both physiological and pathological conditions. Here we overview the recent studies on the structural and biological properties of the membrane interaction by αS. The characterisation of this state is particularly challenging as the membrane binding of αS is weak, transient and features a considerable degree of conformational disorder. Advancements in this area have been achieved through combinations of nuclear magnetic resonance (NMR), super-resolution microscopy, cryo-EM and cellular biophysics. Current data clarified the central role of the equilibrium between ordered and disordered states of αS at the membrane surface, which regulates the membrane affinity, the aggregation into amyloid fibrils and the promotion of vesicle clustering. Recent results on toxic oligomeric species of αS also revealed common features in the membrane interaction of functional and aberrant forms of this protein. These findings therefore evidence the challenging nature of identifying suitable therapeutics to target the aberrant aggregation of αS in PD while leaving its normal physiological form unperturbed.
Topics: Humans; alpha-Synuclein; Protein Binding; Cell Membrane; Parkinson Disease; Magnetic Resonance Spectroscopy
PubMed: 37345454
DOI: 10.1039/d3cc01682j -
Molecular Cell Sep 2023Hsp104 is an AAA+ protein disaggregase that solubilizes and reactivates proteins trapped in aggregated states. We have engineered potentiated Hsp104 variants to mitigate...
Hsp104 is an AAA+ protein disaggregase that solubilizes and reactivates proteins trapped in aggregated states. We have engineered potentiated Hsp104 variants to mitigate toxic misfolding of α-synuclein, TDP-43, and FUS implicated in fatal neurodegenerative disorders. Though potent disaggregases, these enhanced Hsp104 variants lack substrate specificity and can have unfavorable off-target effects. Here, to lessen off-target effects, we engineer substrate-specific Hsp104 variants. By altering Hsp104 pore loops that engage substrate, we disambiguate Hsp104 variants that selectively suppress α-synuclein toxicity but not TDP-43 or FUS toxicity. Remarkably, α-synuclein-specific Hsp104 variants emerge that mitigate α-synuclein toxicity via distinct ATPase-dependent mechanisms involving α-synuclein disaggregation or detoxification of soluble α-synuclein conformers. Importantly, both types of α-synuclein-specific Hsp104 variant reduce dopaminergic neurodegeneration in a C. elegans model of Parkinson's disease more effectively than non-specific variants. We suggest that increasing the substrate specificity of enhanced disaggregases could be applied broadly to tailor therapeutics for neurodegenerative disease.
Topics: Animals; Humans; alpha-Synuclein; Saccharomyces cerevisiae Proteins; Heat-Shock Proteins; Neurodegenerative Diseases; Caenorhabditis elegans
PubMed: 37625404
DOI: 10.1016/j.molcel.2023.07.029 -
International Journal of Molecular... Jul 2023Like many neurodegenerative diseases, Parkinson's disease (PD) is characterized by the formation of proteinaceous aggregates in brain cells. In PD, those proteinaceous... (Review)
Review
Like many neurodegenerative diseases, Parkinson's disease (PD) is characterized by the formation of proteinaceous aggregates in brain cells. In PD, those proteinaceous aggregates are formed by the α-synuclein (αSyn) and are considered the trademark of this neurodegenerative disease. In addition to PD, αSyn pathological aggregation is also detected in atypical Parkinsonism, including Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), as well as neurodegeneration with brain iron accumulation, some cases of traumatic brain injuries, and variants of Alzheimer's disease. Collectively, these (and other) disorders are referred to as synucleinopathies, highlighting the relation between disease type and protein misfolding/aggregation. Despite these pathological relationships, however, synucleinopathies cover a wide range of pathologies, present with a multiplicity of symptoms, and arise from dysfunctions in different neuroanatomical regions and cell populations. Strikingly, αSyn deposition occurs in different types of cells, with oligodendrocytes being mainly affected in MSA, while aggregates are found in neurons in PD. If multiple factors contribute to the development of a pathology, especially in the cases of slow-developing neurodegenerative disorders, the common presence of αSyn aggregation, as both a marker and potential driver of disease, is puzzling. In this review, we will focus on comparing PD, DLB, and MSA, from symptomatology to molecular description, highlighting the role and contribution of αSyn aggregates in each disorder. We will particularly present recent evidence for the involvement of conformational strains of αSyn aggregates and discuss the reciprocal relationship between αSyn strains and the cellular milieu. Moreover, we will highlight the need for effective methodologies for the strainotyping of aggregates to ameliorate diagnosing capabilities and therapeutic treatments.
Topics: Humans; alpha-Synuclein; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Protein Aggregates; Synucleinopathies
PubMed: 37569510
DOI: 10.3390/ijms241512134 -
Current Opinion in Neurology Aug 2024Multiple system atrophy (MSA) is a rapidly progressive synucleinopathy characterized by autonomic failure, parkinsonism, and cerebellar ataxia. Here, we provide an... (Review)
Review
PURPOSE OF REVIEW
Multiple system atrophy (MSA) is a rapidly progressive synucleinopathy characterized by autonomic failure, parkinsonism, and cerebellar ataxia. Here, we provide an update on α-synuclein's role in MSA pathophysiology and review the new Movement Disorders Society (MDS) diagnostic criteria and the utility of α-synuclein-based biomarkers. We also highlight ongoing efforts toward clinical trial readiness and review potential disease-modifying therapies undergoing clinical trials.
RECENT FINDINGS
A role of urinary tract infections in triggering α-synuclein aggregation and contribution of genes implicated in oligodendroglial development have been suggested in the MSA pathophysiology. The clinically probable MSA category of the new diagnostic criteria shows improved accuracy in early disease stages. Predictors of phenoconversion from pure autonomic failure to MSA are now better defined. Alpha-synuclein strains in CSF and serum, phosphorylated α-synuclein deposits in the skin, and brain α-synuclein pathology visualized using PET ligand [18F]ACI-12589 are emerging as valuable diagnostic tools. Clinical trials in MSA investigate drugs targeting α-synuclein aggregation or preventing α-synuclein expression, along with stem cell and gene therapies to halt disease progression.
SUMMARY
New MSA diagnostic criteria and α-synuclein-based biomarkers may enhance diagnostic accuracy while promising therapies are in development to address disease progression.
Topics: Multiple System Atrophy; Humans; alpha-Synuclein; Biomarkers
PubMed: 38828714
DOI: 10.1097/WCO.0000000000001285 -
Biochimica Et Biophysica Acta.... Sep 2023Fibrillary aggregated α-synuclein represents the neurologic hallmark of Parkinson's disease and is considered to play a causative role in the disease. Although the...
Fibrillary aggregated α-synuclein represents the neurologic hallmark of Parkinson's disease and is considered to play a causative role in the disease. Although the causes leading to α-synuclein aggregation are not clear, the GM1 ganglioside interaction is recognized to prevent this process. How GM1 exerts these functions is not completely clear, although a primary role of its soluble oligosaccharide (GM1-OS) is emerging. Indeed, we recently identified GM1-OS as the bioactive moiety responsible for GM1 neurotrophic and neuroprotective properties, specifically reverting the parkinsonian phenotype both in in vitro and in vivo models. Here, we report on GM1-OS efficacy against the α-synuclein aggregation and toxicity in vitro. By amyloid seeding aggregation assay and NMR spectroscopy, we demonstrated that GM1-OS was able to prevent both the spontaneous and the prion-like α-synuclein aggregation. Additionally, circular dichroism spectroscopy of recombinant monomeric α-synuclein showed that GM1-OS did not induce any change in α-synuclein secondary structure. Importantly, GM1-OS significantly increased neuronal survival and preserved neurite networks of dopaminergic neurons affected by α-synuclein oligomers, together with a reduction of microglia activation. These data further demonstrate that the ganglioside GM1 acts through its oligosaccharide also in preventing the α-synuclein pathogenic aggregation in Parkinson's disease, opening a perspective window for GM1-OS as drug candidate.
Topics: Humans; alpha-Synuclein; Parkinson Disease; G(M1) Ganglioside; Oligosaccharides
PubMed: 37330108
DOI: 10.1016/j.bbalip.2023.159350 -
Cell Death & Disease Nov 2023Accumulation of α-synuclein aggregates in the substantia nigra pars compacta is central in the pathophysiology of Parkinson's disease, leading to the degeneration of...
Accumulation of α-synuclein aggregates in the substantia nigra pars compacta is central in the pathophysiology of Parkinson's disease, leading to the degeneration of dopaminergic neurons and the manifestation of motor symptoms. Although several PD models mimic the pathological accumulation of α-synuclein after overexpression, they do not allow for controlling and monitoring its aggregation. We recently generated a new optogenetic tool by which we can spatiotemporally control the aggregation of α-synuclein using a light-induced protein aggregation system. Using this innovative tool, we aimed to characterize the impact of α-synuclein clustering on mitochondria, whose activity is crucial to maintain neuronal survival. We observed that aggregates of α-synuclein transiently and dynamically interact with mitochondria, leading to mitochondrial depolarization, lower ATP production, mitochondrial fragmentation and degradation via cardiolipin externalization-dependent mitophagy. Aggregation of α-synuclein also leads to lower mitochondrial content in human dopaminergic neurons and in mouse midbrain. Interestingly, overexpression of α-synuclein alone did not induce mitochondrial degradation. This work is among the first to clearly discriminate between the impact of α-synuclein overexpression and aggregation on mitochondria. This study thus represents a new framework to characterize the role of mitochondria in PD.
Topics: Animals; Humans; Mice; alpha-Synuclein; Cardiolipins; Dopaminergic Neurons; Mitochondria; Mitophagy; Parkinson Disease; Substantia Nigra
PubMed: 37949858
DOI: 10.1038/s41419-023-06251-8 -
The Lancet. Neurology Nov 2023
Topics: Humans; alpha-Synuclein; Parkinson Disease
PubMed: 37863604
DOI: 10.1016/S1474-4422(23)00373-3 -
Ageing Research Reviews Mar 2024Parkinson's disease (PD) is a neurodegenerative disease with an increased morbidity. The pathogenesis PD has not been fully elucidated, and whatever mechanism is... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disease with an increased morbidity. The pathogenesis PD has not been fully elucidated, and whatever mechanism is involved, it ultimately leads to dopamine (DA) neuronal apoptosis. Cuproptosis is a novel form of cell death. Its morphology, biochemical properties, and mechanism of action differ from known forms of cell death, such as apoptosis, autophagy, necrosis and pyroptosis. Copper binds to the lipoylated components of the tricarboxylic acid cycle, causing proteotoxic stress that ultimately leads to cellular cuproptosis. PD has biochemical features such as mitochondrial dysfunction and decreased levels of copper and glutathione in brain regions. This is closely related to the cuproptosis mechanism. However, the specific link between the pathogenesis of PD and cuproptosis is unclear. Herein, we summarizes cuproptosis as the cause of DA neuronal death in PD, and the relationship between cuproptosis and the PD pathogenesis. This article provides a research basis for targeted cuproptosis for PD.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Neurodegenerative Diseases; Copper; Cell Death; Apoptosis
PubMed: 38311254
DOI: 10.1016/j.arr.2024.102214