Drug Development.

Background: Accumulation of misfolded a-synuclein protein in intracellular inclusion bodies of dopaminergic neurons underlies the pathogenesis of synucleinopathies, which include Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA). Therefore, clearance of misfolded α-synuclein from dopaminergic neurons could in principle offer a an approach for modifying synucleinopathies, which currently remain untreatable.

Method: In this study, we employ the Affinity-directed PROtein Missile (AdPROM) system consisting of the substrate receptor of the CUL2-E3 ligase complex VHL and a nanobody selectively recognising the human α-synuclein protein RESULT: We demonstrate targeted degradation of endogenous α-synuclein from human cell lines with exquisite selectivity.

Host oligodendrogliopathy and α-synuclein strains dictate disease severity in multiple system atrophy.

Multiple system atrophy is a progressive neurodegenerative disease with prominent autonomic and motor features. During early stages, different subtypes of the disease are distinguished by their predominant parkinsonian or cerebellar symptoms, reflecting its heterogeneous nature. The pathognomonic feature of multiple system atrophy is the presence of α-synuclein (αSyn) protein deposits in oligodendroglial cells.

LRRK2 Ablation Attenuates Αlpha-Synuclein-Induced Neuroinflammation Without Affecting Neurodegeneration or Neuropathology In Vivo.

The development of disease-modifying therapies for Parkinson's disease is a major challenge which would be facilitated by a better understanding of the pathogenesis. Leucine-rich repeat kinase 2 (LRRK2) and α-synuclein are key players in Parkinson's disease, but their relationship remains incompletely resolved. Previous studies investigating the effect of LRRK2 on α-synuclein-induced neurotoxicity and neuroinflammation in preclinical Parkinson's disease models have reported conflicting results.

The App mouse retina is a site for preclinical Alzheimer's disease diagnosis and research.

In this study, we report the results of a comprehensive phenotyping of the retina of the App mouse. We demonstrate that soluble Aβ accumulation is present in the retina of these mice early in life and progresses to Aβ plaque formation by midlife. This rising Aβ burden coincides with local microglia reactivity, astrogliosis, and abnormalities in retinal vein morphology.

The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson's disease, multiple system atrophy and dementia with Lewy bodies.

Synucleinopathies, such as Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are defined by the presence of α-synuclein (αSYN) aggregates throughout the nervous system but diverge from one another with regard to their clinical and pathological phenotype. The recent generation of pure fibrillar αSYN polymorphs with noticeable differences in structural and phenotypic traits has led to the hypothesis that different αSYN strains may be in part responsible for the heterogeneous nature of synucleinopathies. To further characterize distinct αSYN strains in the human brain, and establish a structure-pathology relationship, we pursued a detailed comparison of αSYN assemblies derived from well-stratified patients with distinct synucleinopathies.

Mutated ATP10B increases Parkinson's disease risk by compromising lysosomal glucosylceramide export.

Parkinson's disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synuclein-positive Lewy bodies in surviving neurons. Here, we performed whole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6/617 PD patients, 0.

ATP13A2 deficiency disrupts lysosomal polyamine export.

ATP13A2 (PARK9) is a late endolysosomal transporter that is genetically implicated in a spectrum of neurodegenerative disorders, including Kufor-Rakeb syndrome-a parkinsonism with dementia-and early-onset Parkinson's disease. ATP13A2 offers protection against genetic and environmental risk factors of Parkinson's disease, whereas loss of ATP13A2 compromises lysosomes. However, the transport function of ATP13A2 in lysosomes remains unclear.

Linking Neuroinflammation and Neurodegeneration in Parkinson's Disease.

Neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD) impose a pressing burden on our developed and consequently aging society. Misfolded protein aggregates are a critical aspect of several neurodegenerative diseases. Nevertheless, several questions remain unanswered regarding the role of misfolded protein aggregates and the cause of neuronal cell death.

Targeting Neuroinflammation to Treat Alzheimer's Disease.

Over the past few decades, research on Alzheimer's disease (AD) has focused on pathomechanisms linked to two of the major pathological hallmarks of extracellular deposition of beta-amyloid peptides and intra-neuronal formation of neurofibrils. Recently, a third disease component, the neuroinflammatory reaction mediated by cerebral innate immune cells, has entered the spotlight, prompted by findings from genetic, pre-clinical, and clinical studies. Various proteins that arise during neurodegeneration, including beta-amyloid, tau, heat shock proteins, and chromogranin, among others, act as danger-associated molecular patterns, that-upon engagement of pattern recognition receptors-induce inflammatory signaling pathways and ultimately lead to the production and release of immune mediators.

Amylose-lipid complexes as controlled lipid release agents during starch gelatinization and pasting.

The effect of amylose-lipid (AM-L) complexes consisting of amylose populations with different peak degrees of polymerization (DP) and complexed with glyceryl monostearate (GMS) or docosanoic acid (C22) on the pasting properties of wheat and rice starches was evaluated with a rapid visco analyzer (RVA). AM-L complexes were formed by both (i) addition of lipids to amylose fractions with peak DP 20, 60, 400, or 950 at 60 degrees C or (ii) potato phosphorylase-catalyzed amylose synthesis in the presence of lipids. All AM-L complexes affected pasting properties in line with their dissociation characteristics.

Potato phosphorylase catalyzed synthesis of amylose-lipid complexes.

On-line size-exclusion chromatography monitoring of potato phosphorylase catalyzed amylose synthesis--starting from alpha-D-glucose-1-P and maltohexaose--revealed rather monodisperse amylose populations. In the presence of lipids, amylose-lipid complexes spontaneously formed and precipitated. They were recovered by centrifugation, freeze-dried, and characterized by wide-angle X-ray diffraction and differential scanning calorimetry.

Fractionation of starch hydrolysates into dextrins with narrow molecular mass distribution and their detection by high-performance anion-exchange chromatography with pulsed amperometric detection.

Low levels of high-molecular-mass dextrins in starch hydrolysates can be detected by high-performance anion-exchange chromatography with pulsed amperometric detection in spite of their low responses by dialysis of the starch hydrolysate and fractionation of the resulting adialysate with ethanol (final concentration 30-80% at 6 degrees C). In doing so, dextrin fractions with a relatively narrow molecular mass distribution were obtained.