A Novel α-Synuclein K58N Missense Variant in a Patient with Parkinson's Disease.

Background: Parkinson's disease (PD) is a complex multifactorial disorder with a genetic component in about 15% of cases. Multiplications and point mutations in SNCA gene, encoding α-synuclein (aSyn), are linked to rare familial forms of PD.

Objective: Our goal was to assess the clinical presentation and the biological effects of a novel K58N aSyn mutation identified in a patient with PD.

SynapseNet: Deep Learning for Automatic Synapse Reconstruction.

Electron microscopy is an important technique for the study of synaptic morphology and its relation to synaptic function. The data analysis for this task requires the segmentation of the relevant synaptic structures, such as synaptic vesicles, active zones, mitochondria, presynaptic densities, synaptic ribbons, and synaptic compartments. Previous studies were predominantly based on manual segmentation, which is very time-consuming and prevented the systematic analysis of large datasets.

What medicines do people with Parkinson's disease want?

Parkinson's disease (PD) is a heterogeneous condition that presents variable clinical, neuropathological, and biomarker features. Disease progression can also vary significantly. It is essential to consider this heterogeneity when considering the medicines that people with Parkinson's (PwP) want.

Glutamatergic synaptic resilience to overexpressed human alpha-synuclein.

Alpha synuclein (aSyn) is abundant in the brain and strongly implicated in Parkinson's disease (PD), genetically and through its accumulation in neuronal pathognomonic inclusions. While mutations or increased expression of wild-type aSyn can cause familial PD, it remains unclear whether increased aSyn alone impairs presynaptic function. Here, we overexpressed human aSyn (haSyn) in rodent glutamatergic neurons and analysed presynaptic function.

Immunoglobulin divalence promotes B-cell antigen receptor cluster scale-dependent functions.

Antibodies, also known as immunoglobulins, share an evolutionarily conserved dimeric core structure with two antigen binding sites. However, recognition of foreign molecules can be achieved by monovalent binding domains, as evidenced by the T-cell antigen receptor and various innate immune receptors. Thus, the reason for the strict evolutionary conservation of immunoglobulin divalence remains unclear.

Aggregation potency and proinflammatory effects of SARS-CoV-2 proteins.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is primarily known as a respiratory disease. The continued study of the disease has shown that long-term COVID-19 symptoms include persisting effects of the virus on the brain when the infection is over, possibly even leading to neurodegeneration. However, the exact mechanisms of nervous system damage induced by SARS-CoV-2 are still unclear.

Neurodegeneration in Parkinson's disease: are we looking at the right spot?

Parkinson's disease (PD) is recognized as the fastest-growing neurodegenerative disorder, impacting millions of individuals worldwide. It is primarily characterized by cardinal motor symptoms, including bradykinesia (slowness of movement), tremor, rigidity, and postural instability, which significantly impair the quality of life of those affected. Traditionally, the prevailing hypothesis has attributed these motor symptoms to the degeneration and subsequent loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc).

Circadian clock dysfunction in Parkinson's disease: mechanisms, consequences, and therapeutic strategy.

Parkinson's Disease (PD) is a prevalent neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. This leads to hallmark motor features that include bradykinesia, resting tremor, rigidity, and postural instability, alongside with a range of non-motor symptoms including sleep disturbances, mood disorders, and cognitive decline. As global life expectancy rises, the prevalence of PD is expected to continue to increase, highlighting the urgent need for effective therapeutic strategies.

Preface to the Special Issue "History, Biology and Pathobiology of Prions: A Field of Renewed Hopes".

Research in the field of prion diseases has not only shed light on the mechanisms underlying transmissible spongiform encephalopathies (TSEs) but has also influenced the broader understanding of protein misfolding disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and other tauopathies and synucleinopathies. Although prion diseases are rare and invariably fatal, they have provided an invaluable conceptual framework for the study of age-associated neurodegenerative disorders. On the occasion of the "Prion 2023" meeting in Faro, Portugal, which brought together leading experts in prion biology and neurodegeneration to discuss emerging data and evolving concepts, we put together a special issue on the topic to discuss new structural insights, diagnostic technologies, and the increasing recognition of prion-like mechanisms in a wide range of proteinopathies.

Palmitic Acid Induces Dynamic Time-Dependent Alterations in HDACs, Neuronal Chromatin Acetylation, and Gene Expression.

Chronic consumption of high fat diets (HFD) is a risk factor for the development of metabolic diseases such as obesity and diabetes, and it is also associated with cognitive impairment and Alzheimer´s disease. Palmitic acid (PA) is a major component of HFD, and high concentrations of this saturated fatty acid exerts pleiotropic actions in cells. The PA effects have been largely studied in peripheral tissues where is considered a driving force for the development of many metabolic diseases such as obesity, insulin resistance and Type II diabetes.

Endogenous SNAP-Tagging of Munc13‑1 for Monitoring Synapse Nanoarchitecture.

Synaptic function is governed by highly regulated protein machineries, whose abundance and spatial localization change continually. Studies to determine dynamic changes in synaptic protein nanoarchitecture typically rely on immunolabeling or on the expression of fluorescent proteins. The former employs chemical fluorophores and signal amplification but requires fixation.

Gating of hair cell Ca channels governs the activity of cochlear neurons.

Our sense of hearing processes sound intensities spanning six orders of magnitude. In the ear, the receptor potential of presynaptic inner hair cells (IHCs) covers the entire intensity range, while postsynaptic spiral ganglion neurons (SGNs) tile the range with their firing rate codes. IHCs vary the voltage dependence of Ca channel activation among their active zones (AZs), potentially diversifying SGN firing.

Glycation in Alzheimer's Disease and Type 2 Diabetes: The Prospect of Dual Drug Approaches for Therapeutic Interventions.

As global life expectancy increases, the prevalence of neurodegenerative diseases like Alzheimer's disease (AD) continues to rise. Since therapeutic options are minimal, a deeper understanding of the pathophysiology is essential for improved diagnosis and treatments. AD is marked by the aggregation of Aβ proteins, tau hyperphosphorylation, and progressive neuronal loss, though its precise origins remain poorly understood.

Investigation of neuromodulation of the endbulb of Held synapse in the cochlear nucleus by serotonin and norepinephrine.

Introduction: Synapses vary greatly in synaptic strength and plasticity, even within the same circuitry or set of pre- and postsynaptic neurons. Neuromodulation is a candidate mechanism to explain some of this variability. Neuromodulators such as monoamines can differentially regulate presynaptic function and neuronal excitability.

Stress granules: emerging players in neurodegenerative diseases.

Stress granules (SGs) are membraneless organelles formed in the cellular cytoplasm under stressful conditions through liquid-liquid phase separation (LLPS). SG assembly can be both dependent and independent of the eIF2α pathway, whereas cellular protein quality control systems mediate SG disassembly. Chaperones and specific domains of RNA-binding proteins strongly contribute to the regulation SG dynamics.

Lead as an environmental toxicant in models of synucleinopathies.

Lead, a toxic heavy metal, is prevalent in various industrial applications, contributing to environmental contamination and significant health concerns. Lead affects various body systems, especially the brain, causing long-lasting cognitive and behavioral changes. While most studies have focused on continuous lead exposure, intermittent exposure, such as that caused by migration or relocations, has received less attention.

Neural and vascular contributions to sensory impairments in a human alpha-synuclein transgenic mouse model of Parkinson's disease.

Parkinson's disease (PD) is a complex progressive neurodegenerative disorder involving hallmarks such as -Synuclein (Syn) aggregation and dopaminergic dysfunction that affect brain-wide neural activity. Although movement disorders are prominent in PD, sensory impairments also occur relatively early on, mainly in olfactory and, to a lesser extent visual systems. While these deficits have been described mainly at the behavioral and molecular levels, the underlying network-level activity remains poorly understood.

Unconventional Parahydrogen-Induced Hyperpolarization Effects in Chemistry and Catalysis: From Photoreactions to Enzymes.

Nuclear spin hyperpolarization utilizing parahydrogen has the potential for broad applications in chemistry, catalysis, biochemistry, and medicine. This review examines recent chemical and biochemical insights gained using parahydrogen-induced polarization (PHIP). We begin with photoinduced PHIP, which allows the investigation of short-lived and photoactivated catalysis.

Alpha-synuclein aggregation induces prominent cellular lipid changes as revealed by Raman spectroscopy and machine learning analysis.

The aggregation of α-synuclein is a central neuropathological hallmark in neurodegenerative disorders known as Lewy body diseases, including Parkinson's disease and dementia with Lewy bodies. In the aggregation process, α-synuclein transitions from its native disordered/α-helical form to a β-sheet-rich structure, forming oligomers and protofibrils that accumulate into Lewy bodies, in a process that is thought to underlie neurodegeneration. Lipids are thought to play a critical role in this process by facilitating α-synuclein aggregation and contributing to cell toxicity, possibly through ceramide production.

The neurotoxicity of pesticides: Implications for Parkinson's disease.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder worldwide, and no effective cure is currently available. Neuropathologically, PD is characterized by the selective degeneration of dopaminergic neurons in the substantia nigra and by the accumulation of alpha-synuclein (aSyn)-rich proteinaceous inclusions within surviving neurons. As a multifactorial disorder, approximately 85 % of PD cases are sporadic with unknown etiology.

Microtubules as a versatile reference standard for expansion microscopy.

Expansion microscopy (ExM) is continually improving, and new ExM variants need to be validated on well-defined biological structures. There is no consensus on validation structures for ExM, especially as nuclear pore complexes or DNA nanorulers are not popular for ExM studies. Here we propose that microtubules should be used for ExM validation.

A reciprocal relationship between markers of genomic DNA damage and alpha-synuclein pathology in dementia with Lewy bodies.

Background: DNA damage and DNA damage repair (DDR) dysfunction are insults with broad implications for cellular physiology and have been implicated in various neurodegenerative diseases. Alpha-synuclein (aSyn), a pre-synaptic and nuclear protein associated with neurodegenerative disorders known as synucleinopathies, has been associated with DNA double strand break (DSB) repair. However, although nuclear aSyn pathology has been observed in cortical tissue of dementia with Lewy body (DLB) cases, whether such nuclear pathology coincides with the occurrence of DNA damage has not previously been investigated.

3D virtual histology of rodent and primate cochleae with multi-scale phase-contrast X-ray tomography.

Multi-scale X-ray phase contrast tomography (XPCT) enables three-dimensional (3D), non-destructive imaging of intact small animal cochlea and apical cochlear turns. Here we report on post-mortem imaging of excised non-human primate and rodent cochleae at different [Formula: see text]-CT and nano-CT synchrotron instruments. We explore different sample embeddings, stainings and imaging regimes.

Protocol for SUM-PAINT spatial proteomic imaging generating neuronal architecture maps in rat hippocampal neurons.

To unravel the complexity of biological processes, it is necessary to resolve the underlying protein organization down to single proteins. Here, we present a protocol for secondary label-based unlimited multiplexed DNA-PAINT (SUM-PAINT), a DNA-PAINT-based super-resolution microscopy technique that is capable of resolving virtually unlimited protein species with single-protein resolution. We describe the steps to prepare neuronal cultures, troubleshoot and conduct SUM-PAINT experiments, and analyze the resulting feature-rich neuronal cell atlases using unsupervised machine learning approaches.