Potassium Channels in Parkinson's Disease: Potential Roles in Its Pathogenesis and Innovative Molecular Targets for Treatment.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the midbrain. The loss of neurons results in a subsequent reduction of dopamine in the striatum, which underlies the core motor symptoms of PD. To date, there are no effective treatments to stop, slow, or reverse the pathologic progression of dopaminergic neurodegeneration.

Identification of phosphorylated tau protein interactors in progressive supranuclear palsy (PSP) reveals networks involved in protein degradation, stress response, cytoskeletal dynamics, metabolic processes, and neurotransmission.

Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease defined pathologically by the presence of insoluble phosphorylated-Tau (p-Tau) in neurons and glia. Identifying co-aggregating proteins within p-Tau inclusions may reveal important insights into processes affected by the aggregation of Tau. We used a proteomic approach, which combines antibody-mediated biotinylation and mass spectrometry (MS) to identify proteins proximal to p-Tau in PSP.

Glymphatic System Dysfunction and Sleep Disturbance May Contribute to the Pathogenesis and Progression of Parkinson's Disease.

Parkinson's disease (PD) is a multisystem alpha-synucleinopathic neurodegenerative disease and the most prevalent neurodegenerative disorder after Alzheimer's disease with a high incidence rate in the elderly population. PD is highly multifactorial in etiology and has complex and wide-ranging pathogenic mechanisms. Environmental exposures and genetic predisposition are prominent risk factors.

Ferritinophagy and α-Synuclein: Pharmacological Targeting of Autophagy to Restore Iron Regulation in Parkinson's Disease.

A major hallmark of Parkinson's disease (PD) is the fatal destruction of dopaminergic neurons within the . This event is preceded by the formation of Lewy bodies, which are cytoplasmic inclusions composed of α-synuclein protein aggregates. A triad contribution of α-synuclein aggregation, iron accumulation, and mitochondrial dysfunction plague nigral neurons, yet the events underlying iron accumulation are poorly understood.

Oxidative stress and Rho GTPases in the biogenesis of tunnelling nanotubes: implications in disease and therapy.

Tunnelling nanotubes (TNTs) are an emerging route of long-range intercellular communication that mediate cell-to-cell exchange of cargo and organelles and contribute to maintaining cellular homeostasis by balancing diverse cellular stresses. Besides their role in intercellular communication, TNTs are implicated in several ways in health and disease. Transfer of pathogenic molecules or structures via TNTs can promote the progression of neurodegenerative diseases, cancer malignancy, and the spread of viral infection.

Investigating the Convergent Mechanisms between Major Depressive Disorder and Parkinson's Disease.

Major depressive disorder (MDD) affects more than cognition, having a temporal relationship with neuroinflammatory pathways of Parkinson's disease (PD). Although this association is supported by epidemiological and clinical studies, the underlying mechanisms are unclear. Microglia and astrocytes play crucial roles in the pathophysiology of both MDD and PD.

Calcium channels and iron metabolism: A redox catastrophe in Parkinson's disease and an innovative path to novel therapies?

Autonomously spiking dopaminergic neurons of the substantia nigra pars compacta (SNpc) are exquisitely specialized and suffer toxic iron-loading in Parkinson's disease (PD). However, the molecular mechanism involved remains unclear and critical to decipher for designing new PD therapeutics. The long-lasting (L-type) Ca1.

The Effect of Oxidized Dopamine on the Structure and Molecular Chaperone Function of the Small Heat-Shock Proteins, αB-Crystallin and Hsp27.

Oxidation of the neurotransmitter, dopamine (DA), is a pathological hallmark of Parkinson's disease (PD). Oxidized DA forms adducts with proteins which can alter their functionality. αB-crystallin and Hsp27 are intracellular, small heat-shock molecular chaperone proteins (sHsps) which form the first line of defense to prevent protein aggregation under conditions of cellular stress.

Differential Progression of Motor Dysfunction Between Male and Female Fragile X Premutation Carriers Reveals Novel Aspects of Sex-Specific Neural Involvement.

Expansions of the CGG repeat in the non-coding segment of the FMR1 X-linked gene are associated with a variety of phenotypic changes. Large expansions (>200 repeats), which cause a severe neurodevelopmental disorder, the fragile x syndrome (FXS), are transmitted from the mothers carrying smaller, unstable expansions ranging from 55 to 200 repeats, termed the fragile X premutation. Female carriers of this premutation may themselves experience a wide range of clinical problems throughout their lifespan, the most severe being the late onset neurodegenerative condition called "Fragile X-Associated Tremor Ataxia Syndrome" (FXTAS), occurring between 8 and 16% of these carriers.

Alpha-Synuclein Aggregates Associated with Mitochondria in Tunnelling Nanotubes.

The interaction of α-synuclein with mitochondria in both typical and atypical Parkinson's disease is a critical component of degeneration. The mechanism of cell-to-cell propagation of pathological α-synuclein in synucleinopathies is unclear. Intercellular exchange of mitochondria along tunnelling nanotubes has been described in other diseases, such as cancer; however, its role in synucleinopathies is unknown.

Extracellular Alpha-Synuclein Promotes a Neuroinhibitory Secretory Phenotype in Astrocytes.

Multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) are α-synucleinopathies that exhibit widespread astrogliosis as a component of the neuroinflammatory response. Munc18, a protein critical to vesicle exocytosis, was previously found to strongly mark morphologically activated astrocytes in brain tissue of MSA patients. Immunofluorescence of MSA, DLB and normal brain tissue sections was combined with cell culture and co-culture experiments to investigate the relationship between extracellular α-synuclein and the transition to a secretory astrocyte phenotype.

Isotope metallomics approaches for medical research.

Metallomics is a rapidly evolving field of bio-metal research that integrates techniques and perspectives from other "-omics" sciences (e.g. genomics, proteomics) and from research vocations further afield.

Ginkgolic acid promotes autophagy-dependent clearance of intracellular alpha-synuclein aggregates.

The accumulation of intracytoplasmic inclusion bodies (Lewy bodies) composed of aggregates of the alpha-synuclein (α-syn) protein is the principal pathological characteristic of Parkinson's disease (PD) and may lead to degeneration of dopaminergic neurons. To date there is no medication that can promote the efficient clearance of these pathological aggregates. In this study, the effect on α-syn aggregate clearance of ginkgolic acid (GA), a natural compound extracted from Ginkgo biloba leaves that inhibits SUMOylation amongst other pathways, was assessed in SH-SY5Y neuroblastoma cells and rat primary cortical neurons.

Intracellular and Intercellular Mitochondrial Dynamics in Parkinson's Disease.

The appearance of alpha-synuclein-positive inclusion bodies (Lewy bodies) and the loss of catecholaminergic neurons are the primary pathological hallmarks of Parkinson's disease (PD). However, the dysfunction of mitochondria has long been recognized as a key component in the progression of the disease. Dysfunctional mitochondria can in turn lead to dysregulation of calcium homeostasis and, especially in dopaminergic neurons, raised mean intracellular calcium concentration.

Switching on Endogenous Metal Binding Proteins in Parkinson's Disease.

The formation of cytotoxic intracellular protein aggregates is a pathological signature of multiple neurodegenerative diseases. The principle aggregating protein in Parkinson's disease (PD) and atypical Parkinson's diseases is α-synuclein (α-syn), which occurs in neural cytoplasmic inclusions. Several factors have been found to trigger α-syn aggregation, including raised calcium, iron, and copper.

Extracellular Interactions of Alpha-Synuclein in Multiple System Atrophy.

Multiple system atrophy, characterized by atypical Parkinsonism, results from central nervous system (CNS) cell loss and dysfunction linked to aggregates of the normally pre-synaptic α-synuclein protein. Mostly cytoplasmic pathological α-synuclein inclusion bodies occur predominantly in oligodendrocytes in affected brain regions and there is evidence that α-synuclein released by neurons is taken up preferentially by oligodendrocytes. However, extracellular α-synuclein has also been shown to interact with other neural cell types, including astrocytes and microglia, as well as extracellular factors, mediating neuroinflammation, cell-to-cell spread and other aspects of pathogenesis.

Epothilone D inhibits microglia-mediated spread of alpha-synuclein aggregates.

Multiple System Atrophy (MSA) is a progressive neurodegenerative disease characterized by chronic neuroinflammation and widespread α-synuclein (α-syn) cytoplasmic inclusions. Neuroinflammation associated with microglial cells is typically located in brain regions with α-syn deposits. The potential link between microglial cell migration and the transport of pathological α-syn protein in MSA was investigated.

SUMOylation, aging and autophagy in neurodegeneration.

Protein homeostasis is essential for the wellbeing of several cellular systems. Post-translational modifications (PTM) coordinate various pathways in response to abnormal aggregation of proteins in neurodegenerative disease states. In the presence of accumulating misfolded proteins and toxic aggregates, the small ubiquitin-like modifier (SUMO) is associated with various substrates, including chaperones and other recruited factors, for refolding and for clearance via proteolytic systems, such as the ubiquitin-proteasome pathway (UPS), chaperone-mediated autophagy (CMA) and macroautophagy.

Chemistry of mammalian metallothioneins and their interaction with amyloidogenic peptides and proteins.

Cu and Zn ions are essential in most living beings. Their metabolism is critical for health and mis-metabolism can be lethal. In the last two decades, a large body of evidence has reported the role of copper, zinc and iron, and oxidative stress in several neurodegenerative diseases like Alzheimer's, Parkinson's, prion diseases, etc.

Dexamethasone Inhibits Copper-Induced Alpha-Synuclein Aggregation by a Metallothionein-Dependent Mechanism.

Intracellular aggregates of α-synuclein are the pathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), being linked to neurotoxicity. Multiple triggers of α-synuclein aggregation have been implicated, including raised copper. The potential protective role of the endogenous copper-/zinc-binding proteins, metallothioneins (MT), has been explored in relation to copper-induced α-synuclein aggregation.

Metallothionein, Copper and Alpha-Synuclein in Alpha-Synucleinopathies.

Metallothioneins (MTs) are proteins that function by metal exchange to regulate the bioavailability of metals, such as zinc and copper. Copper functions in the brain to regulate mitochondria, neurotransmitter production, and cell signaling. Inappropriate copper binding can result in loss of protein function and Cu(I)/(II) redox cycling can generate reactive oxygen species.

Potential Modes of Intercellular α-Synuclein Transmission.

Intracellular aggregates of the α-synuclein protein result in cell loss and dysfunction in Parkinson's disease and atypical Parkinsonism, such as multiple system atrophy and dementia with Lewy bodies. Each of these neurodegenerative conditions, known collectively as α-synucleinopathies, may be characterized by a different suite of molecular triggers that initiate pathogenesis. The mechanisms whereby α-synuclein aggregates mediate cytotoxicity also remain to be fully elucidated.

Calcipotriol inhibits α-synuclein aggregation in SH-SY5Y neuroblastoma cells by a Calbindin-D28k-dependent mechanism.

Many neurodegenerative diseases are characterized by the formation of microscopically visible intracellular protein aggregates. α-Synuclein is the key aggregating protein in Parkinson's disease which is characterized by neuronal cytoplasmic Lewy body inclusions. Previous studies have shown relative sparing of neurons in Parkinson's disease and dementia with Lewy bodies that are positive for the vitamin D-dependent calcium-buffering protein, calbindin-D28k, and that α-synuclein aggregates are excluded from calbindin-D28k-positive neurons.

Calcium: Alpha-Synuclein Interactions in Alpha-Synucleinopathies.

Aggregation of the pre-synaptic protein, α-synuclein (α-syn), is the key etiological factor in Parkinson's disease (PD) and other alpha-synucleinopathies, such as multiple system atrophy (MSA) and Dementia with Lewy bodies (DLB). Various triggers for pathological α-syn aggregation have been elucidated, including post-translational modifications, oxidative stress, and binding of metal ions, such as calcium. Raised neuronal calcium levels in PD may occur due to mitochondrial dysfunction and/or may relate to calcium channel dysregulation or the reduced expression of the neuronal calcium buffering protein, calbindin-D28k.