Alpha-synuclein aggregates activate calcium pump SERCA leading to calcium dysregulation.

Aggregation of α-synuclein is a hallmark of Parkinson's disease and dementia with Lewy bodies. We here investigate the relationship between cytosolic Ca and α-synuclein aggregation. Analyses of cell lines and primary culture models of α-synuclein cytopathology reveal an early phase with reduced cytosolic Ca levels followed by a later Ca increase.

Axonal dystrophy in the brain of mice with Sanfilippo syndrome.

Axonal dystrophy has been described as an early pathological feature of neurodegenerative disorders including Alzheimer's disease and amyotrophic lateral sclerosis. Axonal inclusions have also been reported to occur in several neurodegenerative lysosomal storage disorders including Mucopolysaccharidosis type IIIA (MPS IIIA; Sanfilippo syndrome). This disorder results from a mutation in the gene encoding the lysosomal sulphatase sulphamidase, and as a consequence heparan sulphate accumulates, accompanied by secondarily-stored gangliosides.

Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein.

The aggregation of α-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson's disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT aSyn aggregates are unclear.

Interference of α-Synuclein Uptake by Monomeric β-Amyloid1-40 and Potential Core Acting Site of the Interference.

Increasing evidence suggests an important role of alpha-synuclein (α-Syn) in the pathogenesis of Parkinson's disease (PD). The inter-neuronal spread of α-Syn via exocytosis and endocytosis has been proposed as an explanation for the neuropathological findings of PD in sub-clinical and clinical phases. Therefore, interfering the uptake of α-Syn by neurons may be an important step in slowing or modifying the propagation of the disease.

Quantitative protein profiling of hippocampus during human aging.

The hippocampus appears commonly affected by aging and various neurologic disorders in humans, whereas little is known about age-related change in overall protein expression in this brain structure. Using the 4-plex tandem mass tag labeling, we carried out a quantitative proteomic study of the hippocampus during normal aging using postmortem brains from Chinese subjects. Hippocampal samples from 16 subjects died of non-neurological/psychiatric diseases were divided into 4 age groups: 22-49, 50-69, 70-89, and >90.

Neuroprotective Activities of Marine Natural Products from Marine Sponges.

This review covers the compounds isolated from marine sponges with neuroprotective activities during the period between 1999 and 2014 based on their chemical structures, collections sites, sponge taxonomy and neuroprotective effects. These compounds were isolated from marine sponges collected from 18 countries, most of them in Indonesia, followed by Japan. A total of 90 compounds were reported to exhibit a range of neuroprotective efficacy.

Aggregation-induced emission fluorogens as biomarkers to assess the viability of microalgae in aquatic ecosystems.

Microalgae can be a valuable indicator for monitoring water pollution due to their sensitivity to the changes induced by pollutants in the environment. In this study, an aggregation-induced emission fluorogen was used as a novel tool to differentiate dead and live microalgae and quantify the link between live algal concentration and fluorogen intensity. Protein in the cell protoplasm is the key component contributing to fluorescence emission in algae.

Generation and characterization of novel conformation-specific monoclonal antibodies for α-synuclein pathology.

α-Synuclein (α-syn), a small protein that has the intrinsic propensity to aggregate, is implicated in several neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are collectively known as synucleinopathies. Genetic, pathological, biochemical, and animal modeling studies provided compelling evidence that α-syn aggregation plays a key role in the pathogenesis of PD and related synucleinopathies. It is therefore of utmost importance to develop reliable tools that can detect the aggregated forms of α-syn.

Non-neuronal and neuronal BACE1 elevation in association with angiopathic and leptomeningeal β-amyloid deposition in the human brain.

Background: Cerebral amyloid angiopathy (CAA) refers to the deposition of β-amyloid (Aβ) peptides in the wall of brain vasculature, commonly involving capillaries and arterioles. Also being considered a part of CAA is the Aβ deposition in leptomeninge. The cellular origin of angiopathic Aβ and the pathogenic course of CAA remain incompletely understood.

The degree of astrocyte activation in multiple system atrophy is inversely proportional to the distance to α-synuclein inclusions.

Multiple system atrophy (MSA) exhibits widespread astrogliosis together with α-synuclein (α-syn) glial cytoplasmic inclusions (GCIs) in mature oligodendrocytes. We quantified astrocyte activation by morphometric analysis of MSA cases, and investigated the correlation to GCI proximity. Using Imaris software, we obtained "skinned" three-dimensional models of GFAP-positive astrocytes in MSA and control tissue (n=75) from confocal z-stacks and measured the astrocyte process length and thickness and radial distance to the GCI.

Identification of synaptosomal proteins binding to monomeric and oligomeric α-synuclein.

Monomeric α-synuclein (αSN) species are abundant in nerve terminals where they are hypothesized to play a physiological role related to synaptic vesicle turn-over. In Parkinson's disease (PD) and dementia with Lewy body (DLB), αSN accumulates as aggregated soluble oligomers in terminals, axons and the somatodendritic compartment and insoluble filaments in Lewy inclusions and Lewy neurites. The autosomal dominant heritability associated to mutations in the αSN gene suggest a gain of function associated to aggregated αSN.

Detection of oligomers and fibrils of α-synuclein by AIEgen with strong fluorescence.

We report a fluorophore, TPE-TPP, with AIE characteristics which is utilized as a fluorescence probe to monitor the α-synuclein (α-Syn) fibrillation process. Compared with ThT, TPE-TPP shows a higher sensitivity in the detection of α-Syn oligomers as well as fibrils with a stronger fluorescence. The performance of TPE-TPP was evaluated using fluorescence, AFM, dot blot, and SEC.

Dipeptidyl peptidase 10 (DPP10(789)): a voltage gated potassium channel associated protein is abnormally expressed in Alzheimer's and other neurodegenerative diseases.

The neuropathological features associated with Alzheimer's disease (AD) include the presence of extracellular amyloid-β peptide-containing plaques and intracellular tau positive neurofibrillary tangles and the loss of synapses and neurons in defined regions of the brain. Dipeptidyl peptidase 10 (DPP10) is a protein that facilitates Kv4 channel surface expression and neuronal excitability. This study aims to explore DPP10789 protein distribution in human brains and its contribution to the neurofibrillary pathology of AD and other tauopathies.

Evidence that the LRRK2 ROC domain Parkinson's disease-associated mutants A1442P and R1441C exhibit increased intracellular degradation.

Mutations in the leucine-rich repeat kinase 2 (lrrk2) gene are the leading genetic cause of Parkinson's disease (PD). In characterizing the novel ROC domain mutant A1442P, we compared its steady-state protein levels, propensity to aggregate, and toxicity with the pathogenic R1441C mutant and wild-type (WT) LRRK2. Mutant (R1441C and A1442P) and WT LRRK2 fused to green fluorescent protein (GFP) and FLAG were transiently expressed in HEK293 cells using plasmid constructs.

Uptake and mitochondrial dysfunction of alpha-synuclein in human astrocytes, cortical neurons and fibroblasts.

The accumulation and aggregation of alpha-synuclein (α-syn) in several tissue including the brain is a major pathological hallmark in Parkinson's disease (PD). In this study, we show that α-syn can be taken up by primary human cortical neurons, astrocytes and skin-derived fibroblasts in vitro. Our findings that brain and peripheral cells exposed to α-syn can lead to impaired mitochondrial function, leading to cellular degeneration and cell death, provides additional evidence for the involvement of mitochondrial dysfunction as a mechanism of toxicity of α-syn in human cells.

Can BACE1 inhibition mitigate early axonal pathology in neurological diseases?

β-Secretase-1 (BACE1) is the rate-limiting enzyme for the genesis of amyloid-β (Aβ) peptides, the main constituents of the amyloid plaques in the brains of Alzheimer's disease (AD) patients. BACE1 is being evaluated as an anti-Aβ target for AD therapy. Recent studies indicate that BACE1 elevation is associated with axonal and presynaptic pathology during plaque development.

Alpha-synuclein transmission and mitochondrial toxicity in primary human foetal enteric neurons in vitro.

Parkinson's disease (PD) is a multicentred neurodegenerative disorder characterised by the accumulation and aggregation of alpha-synuclein (α-syn) in several parts of the central nervous system. However, it is well established that PD can generate symptoms of constipation and other gastrointestinal problems and α-syn containing lesions have been identified in intestinal nerve cells. In this study, we show that α-syn can be taken up and accumulate in primary human foetal enteric neurons from the gastrointestinal tract and can be transferred between foetal enteric neurons.

Amyloid beta₁₋₄₂ (Aβ₄₂) up-regulates the expression of sortilin via the p75(NTR)/RhoA signaling pathway.

Sortilin, a Golgi sorting protein and a member of the VPS10P family, is the co-receptor for proneurotrophins, regulates protein trafficking, targets proteins to lysosomes, and regulates low density lipoprotein metabolism. The aim of this study was to investigate the expression and regulation of sortilin in Alzheimer's disease (AD). A significantly increased level of sortilin was found in human AD brain and in the brains of 6-month-old swedish-amyloid precursor protein/PS1dE9 transgenic mice.

Tenuigenin attenuates α-synuclein-induced cytotoxicity by down-regulating polo-like kinase 3.

Background And Aims: Tenuigenin (Ten) is a Chinese herbal extract with antioxidative and antiinflammatory effects on toxin-induced cell models of Parkinson's disease (PD); however, its effects on α-synuclein toxicity-based PD models remain unknown. α-synuclein hyperphosphorylation is a key event in PD pathogenesis and potential target of therapeutic interventions. We tested whether Ten alleviates α-synuclein-induced cytotoxicity via reducing kinases that phosphorylate α-synuclein.

FAS-dependent cell death in α-synuclein transgenic oligodendrocyte models of multiple system atrophy.

Multiple system atrophy is a parkinsonian neurodegenerative disorder. It is cytopathologically characterized by accumulation of the protein p25α in cell bodies of oligodendrocytes followed by accumulation of aggregated α-synuclein in so-called glial cytoplasmic inclusions. p25α is a stimulator of α-synuclein aggregation, and coexpression of α-synuclein and p25α in the oligodendroglial OLN-t40-AS cell line causes α-synuclein aggregate-dependent toxicity.

Selective coexpression of synaptic proteins, α-synuclein, cysteine string protein-α, synaptophysin, synaptotagmin-1, and synaptobrevin-2 in vesicular acetylcholine transporter-immunoreactive axons in the guinea pig ileum.

Parkinson's disease is a neurodegenerative disorder characterized by Lewy bodies and neurites composed mainly of the presynaptic protein α-synuclein. Frequently, Lewy bodies and neurites are identified in the gut of Parkinson's disease patients and may underlie associated gastrointestinal dysfunctions. We recently reported selective expression of α-synuclein in the axons of cholinergic neurons in the guinea pig and human distal gut; however, it is not clear whether α-synuclein expression varies along the gut, nor how closely expression is associated with other synaptic proteins.

SUMO-1 is associated with a subset of lysosomes in glial protein aggregate diseases.

Oligodendroglial inclusion bodies characterize a subset of neurodegenerative diseases. Multiple system atrophy (MSA) is characterized by α-synuclein glial cytoplasmic inclusions and progressive supranuclear palsy (PSP) is associated with glial tau inclusions. The ubiquitin homologue, SUMO-1, has been identified in inclusion bodies in MSA, located in discrete sub-domains in α-synuclein-positive inclusions.

LRRK2 interactions with α-synuclein in Parkinson's disease brains and in cell models.

Mutations in the genes encoding leucine-rich repeat kinase 2 (LRRK2) and α-synuclein are associated with both autosomal dominant and idiopathic forms of Parkinson's disease (PD). α-Synuclein is the main protein in Lewy bodies, hallmark inclusions present in both sporadic and familial PD. We show that in PD brain tissue, the levels of LRRK2 are positively related to the increase in α-synuclein phosphorylation and aggregation in affected brain regions (amygdala and anterior cingulate cortex), but not in the unaffected visual cortex.