Accumulation of alpha-synuclein pathology in the liver exhibits post-translational modifications associated with Parkinson's disease.

Accumulating evidence demonstrates that alpha-synuclein (α-syn) pathology associated with Parkinson's disease (PD) is not limited to the brain, as it also appears in a select number of peripheral tissues including the liver. In this study, we identified a number of PD-associated α-syn post-translational modifications in the livers of (Thy-1)-h[A30P] mice, a mouse model of familial PD expressing human α-syn harboring the A30P mutation driven by a neuron-specific promoter. , we also demonstrate that human hepatocytes induce post-translational modifications following α-syn fibrillar (PFF) treatment.

Lack of cellular prion protein causes Amyloid β accumulation, increased extracellular vesicle abundance, and changes to exosome biogenesis proteins.

Alzheimer's disease (AD) progression is closely linked to the propagation of pathological Amyloid β (Aβ), a process increasingly understood to involve extracellular vesicles (EVs), namely exosomes. The specifics of Aβ packaging into exosomes remain elusive, although evidence suggests an ESCRT (Endosomal Sorting Complex Required for Transport)-independent origin to be responsible in spreading of AD pathogenesis. Intriguingly, PrP, known to influence exosome abundance and bind oligomeric Aβ (oAβ), can be released in exosomes via both ESCRT-dependent and ESCRT-independent pathways, raising questions about its role in oAβ trafficking.

Exposure of α-Synuclein Aggregates to Organotypic Slice Cultures Recapitulates Key Molecular Features of Parkinson's Disease.

The accumulation of proteinaceous deposits comprised largely of the α-synuclein protein is one of the main hallmarks of Parkinson's disease (PD) and related synucleinopathies. Their progressive development coincides with site-specific phosphorylation, oxidative stress and eventually, compromised neuronal function. However, modeling protein aggregate formation in animal or models has proven notably difficult.

Parkinson's disease and multiple system atrophy patient iPSC-derived oligodendrocytes exhibit alpha-synuclein-induced changes in maturation and immune reactive properties.

SignificanceOur results demonstrate the existence of early cellular pathways and network alterations in oligodendrocytes in the alpha-synucleinopathies Parkinson's disease and multiple system atrophy. They further reveal the involvement of an immune component triggered by alpha-synuclein protein, as well as a connection between (epi)genetic changes and immune reactivity in multiple system atrophy. The knowledge generated in this study could be used to devise novel therapeutic approaches to treat synucleinopathies.

Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson's disease.

Alpha-synuclein (α-syn) aggregation is the hallmark pathological lesion in brains of patients with Parkinson's disease (PD) and related neurological disorders characterized as synucleinopathies. Accumulating evidence now indicates that α-syn deposition is also present within the gut and other peripheral organs outside the central nervous system (CNS). In the current study, we demonstrate for the first time that α-syn pathology also accumulates within the liver, the main organ responsible for substance clearance and detoxification.

Binding of α-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes.

The intercellular transfer of alpha-synuclein (α-syn) has been implicated in the progression of Parkinson's disease (PD) and multiple system atrophy (MSA). The cellular mechanisms underlying this process are now beginning to be elucidated. In this study, we demonstrate that the gap junction protein connexin-32 (Cx32) is centrally involved in the preferential uptake of α-syn oligomeric assemblies (oα-syn) in neurons and oligodendrocytes.

Reduced retromer function results in the accumulation of amyloid-beta oligomers.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of multiple cognitive functions. Accumulation of amyloid beta oligomers (oAβ) play a major role in the neurotoxicity associated with the disease process. One of the early affected brain regions is the hippocampus, wherein a reduction of the vacuolar protein sorting-associated protein 35 (VPS35), the core protein comprising the retromer complex involved in cellular cargo sorting, has been identified.

Label-free concentration of viable neurons, hESCs and cancer cells by means of acoustophoresis.

Concentration of viable cell populations in suspension is of interest for several clinical and pre-clinical applications. Here, we report that microfluidic acoustophoresis is an effective method to efficiently concentrate live and viable cells with high target purity without any need for protein fluorescent labeling using antibodies or over-expression. We explored the effect of the acoustic field acoustic energy density and systematically used different protocols to induce apoptosis or cell death and then determined the efficiency of live and dead cell separation.

The role of Galectin-3 in α-synuclein-induced microglial activation.

Background: Parkinson's disease (PD) is the most prevalent neurodegenerative motor disorder. The neuropathology is characterized by intraneuronal protein aggregates of α-synuclein and progressive degeneration of dopaminergic neurons within the substantia nigra. Previous studies have shown that extracellular α-synuclein aggregates can activate microglial cells, induce inflammation and contribute to the neurodegenerative process in PD.

A cell culture model for monitoring α-synuclein cell-to-cell transfer.

The transfer of α-synuclein (α-syn) between cells has been proposed to be the primary mechanism of disease spreading in Parkinson's disease. Several cellular models exist that monitor the uptake of recombinant α-syn from the culture medium. Here we established a more physiologically relevant model system in which α-syn is produced and transferred between mammalian neurons.

Alpha-synuclein transfers from neurons to oligodendrocytes.

The origin of α-synuclein (α-syn)-positive glial cytoplasmic inclusions found in oligodendrocytes in multiple system atrophy (MSA) is enigmatic, given the fact that oligodendrocytes do not express α-syn mRNA. Recently, neuron-to-neuron transfer of α-syn was suggested to contribute to the pathogenesis of Parkinson's disease. In this study, we explored whether a similar transfer of α-syn might occur from neurons to oligodendrocytes, which conceivably could explain how glial cytoplasmic inclusions are formed.

Can Parkinson's disease pathology be propagated from one neuron to another?

Parkinson's disease is the second most prevalent neurodegenerative disease, yet despite this, very little is known about the underlying cellular mechanisms. Initially it was thought to be a disease primarily involving loss of dopaminergic neurons in the substantia nigra pars compacta. Recent studies, however, have focused on observations that aggregated α-synuclein protein, the major component of Lewy bodies, is found throughout the nervous system.

Selective tau tyrosine nitration in non-AD tauopathies.

Previously, we reported the characterization of two novel antibodies that react with tau nitrated at tyrosine 197 (Tau-nY197) and tyrosine 394 (Tau-nY394) in Alzheimer's disease (AD). In this report, we examined whether tau nitration at these sites also occurs in corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and Pick's disease (PiD), three neurodegenerative tauopathies that contain abundant tau deposits within glial and neuronal cell types but lack amyloid deposition. The reactivity of these antibodies was also compared to two previously characterized antibodies Tau-nY18 and Tau-nY29, specific for tau nitrated at tyrosine 18 and tyrosine 29, respectively.

Tyrosine nitration within the proline-rich region of Tau in Alzheimer's disease.

A substantial body of evidence suggests that nitrative injury contributes to neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative disorders. Previously, we showed in vitro that within the tau protein the N-terminal tyrosine residues (Y18 and Y29) are more susceptible to nitrative modifications than other tyrosine sites (Y197 and Y394). Using site-specific antibodies to nitrated tau at Y18 and Y29, we identified tau nitrated in both glial (Y18) and neuronal (Y29) tau pathologies.

Formation of Hirano bodies after inducible expression of a modified form of an actin-cross-linking protein.

Hirano bodies are cytoplasmic inclusions composed mainly of actin and actin-associated proteins. The formation of Hirano bodies during various neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis, has been reported. Although the underlying molecular mechanisms that lead to the formation of these inclusions in the brain are not known, expression of the C-terminal fragment (CT) (amino acids 124 to 295) from the endogenous 34-kDa actin-binding protein of Dictyostelium discoideum leads to the formation of actin inclusions in vivo.

A possible link between astrocyte activation and tau nitration in Alzheimer's disease.

Alzheimer's disease (AD) pathology has been characterized, in part, by the self-assembly of the tau molecule into neurofibrillary tangles (NFT). While different post-translational modifications have been identified that accelerate tau aggregation, nitration at tyrosine residues prevents or slows tau filament formation in vitro. Of the five tyrosine residues within the molecule, nitration at the first tyrosine residue (Tyr 18) results in a profound inhibition of filament self-assembly.

Road building, land use and climate change: prospects for environmental governance in the Amazon.

Some coupled land-climate models predict a dieback of Amazon forest during the twenty-first century due to climate change, but human land use in the region has already reduced the forest cover. The causation behind land use is complex, and includes economic, institutional, political and demographic factors. Pre-eminent among these factors is road building, which facilitates human access to natural resources that beget forest fragmentation.

Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer's disease and other tauopathies.

The neurodegenerative tauopathies are a clinically diverse group of diseases typified by the pathological self-assembly of the microtubule-associated tau protein. Although tau nitration is believed to influence the pathogenesis of these diseases, the precise residues modified, and the resulting effects on tau function, remain enigmatic. Previously, we demonstrated that nitration at residue Tyr29 markedly inhibits the ability of tau to self-associate and stabilize the microtubule lattice (Reynolds et al.