Ultrastructural pathology of anaplastic and grade II ependymomas reveals distinctive ciliary structures--electron microscopy redux.

Ependymoma tumors likely derive from the ependymal cells lining the CNS ventricular system. In grade II ependymomas, tumor cells resemble typical ependymocytes, while anaplastic ependymomas are poorly differentiated. We studied three grade II and one anaplastic ependymoma, focusing on the ciliary structures. To unambiguously characterize the ultrastructure and number of cilia, we performed electron microscopy serial section analysis of individual cells. Differentiated ependymomas contained large basal bodies and up to three cilia, and lacked centrioles. Anaplastic ependymoma cells showed instead two perpendicularly oriented centrioles and lacked cilia or basal bodies. These findings could contribute to understand the mechanisms of ependymoma aggressiveness.

Targeting the Cysteine Redox Proteome in Parkinson's Disease: The Role of Glutathione Precursors and Beyond.

Encouraging recent data on the molecular pathways underlying aging have identified variants and expansions of genes associated with DNA replication and repair, telomere and stem cell maintenance, regulation of the redox microenvironment, and intercellular communication. In addition, cell rejuvenation requires silencing some transcription factors and the activation of pluripotency, indicating that hidden molecular networks must integrate and synchronize all these cellular mechanisms. Therefore, in addition to gene sequence expansions and variations associated with senescence, the optimization of transcriptional regulation and protein crosstalk is essential. The protein cysteinome is crucial in cellular regulation and plays unexpected roles in the aging of complex organisms, which show cumulative somatic mutations, telomere attrition, epigenetic modifications, and oxidative dysregulation, culminating in cellular senescence. The cysteine thiol groups are highly redox-active, allowing high functional versatility as structural disulfides, redox-active disulfides, active-site nucleophiles, proton donors, and metal ligands to participate in multiple regulatory sites in proteins. Also, antioxidant systems control diverse cellular functions, including the transcription machinery, which partially depends on the catalytically active cysteines that can reduce disulfide bonds in numerous target proteins, driving their biological integration. Since we have previously proposed a fundamental role of cysteine-mediated redox deregulation in neurodegeneration, we suggest that cellular rejuvenation of the cysteine redox proteome using GSH precursors, like N-acetyl-cysteine, is an underestimated multitarget therapeutic approach that would be particularly beneficial in Parkinson's disease.

N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases.

In the last twenty years, significant progress in understanding the pathophysiology of age-associated neurodegenerative diseases has been made. However, the prevention and treatment of these diseases remain without clinically significant therapeutic advancement. While we still hope for some potential genetic therapeutic approaches, the current reality is far from substantial progress. With this state of the issue, emphasis should be placed on early diagnosis and prompt intervention in patients with increased risk of neurodegenerative diseases to slow down their progression, poor prognosis, and decreasing quality of life. Accordingly, it is urgent to implement interventions addressing the psychosocial and biochemical disturbances we know are central in managing the evolution of these disorders. Genomic and proteomic studies have shown the high molecular intricacy in neurodegenerative diseases, involving a broad spectrum of cellular pathways underlying disease progression. Recent investigations indicate that the dysregulation of the sensitive-cysteine proteome may be a concurrent pathogenic mechanism contributing to the pathophysiology of major neurodegenerative diseases, opening new therapeutic opportunities. Considering the incidence and prevalence of these disorders and their already significant burden in Western societies, they will become a real pandemic in the following decades. Therefore, we propose large-scale investigations, in selected groups of people over 40 years of age with decreased blood glutathione levels, comorbidities, and/or mild cognitive impairment, to evaluate supplementation of the diet with low doses of N-acetyl-cysteine, a promising and well-tolerated therapeutic agent suitable for long-term use.

Interfering with the Reactive Cysteine Proteome in COVID-19.

Although vaccination against SARS-CoV-2 infection has been initiated, effective therapies for severe COVID-19 disease are still needed. A promising therapeutic strategy is using FDA-approved drugs that have the biological potential to interfere with or modify some of the viral proteins capable of changing the disease's course. Recent studies highlight that some clinically safe drugs can suppress the viral life cycle while potentially promoting an adequate host inflammatory/immune response by interfering with the disease's cysteine proteome.

Proteomic Complexity in Parkinson's Disease: A Redox Signaling Perspective of the Pathophysiology and Progression.

Parkinson's disease (PD) is a prevalent age-related neurodegenerative disorder that results in the progressive impairment of motor and cognitive functions. The majority of PD cases are sporadic, and only 5% of patients are associated with mutations in a few genes, which cause the early onset or familial PD. Environmental toxic substances and the individual genetic susceptibility play a role in sporadic cases, but despite significant efforts to treat and prevent the disease, the pathophysiological mechanisms leading to its onset and progress are not fully understood. In the last decade, genomic and proteomic studies have shown an increasing molecular complexity of sporadic PD, suggesting that a broad spectrum of biochemical pathways underlie its progression. Recent investigations and the literature review suggest the potential role of deregulation of the sensitive-cysteine proteome as a convergent pathogenic mechanism that may contribute to this complexity, opening new therapeutic opportunities.

N-acetyl-cysteine in Schizophrenia: Potential Role on the Sensitive Cysteine Proteome.

BACKGROUND: N-acetyl-cysteine (NAC) has shown widespread utility in different psychiatric disorders, including a beneficial role in schizophrenic patients. Although the replenishment of glutathione and the antioxidant activity of NAC have been suggested as the mechanisms that improve such a wide range of disorders, none seems to be sufficiently specific to explain these intriguing effects. A sensitive cysteine proteome is emerging as a functional and structural network of interconnected Sensitive Cysteine-containing Proteins (SCCPs) that together with reactive species and the cysteine/ glutathione cycles can regulate the bioenergetic metabolism, the redox homeostasis and the cellular growth, differentiation and survival, acting through different pathways that are regulated by the same thiol radical in cysteine residues. OBJECTIVE: Since this sensitive cysteine network has been implicated in the pathogenesis of Parkinson's and Alzheimer's diseases, I have reviewed if the proteins that play a role in schizophrenia can be classified as SCCPs. RESULTS: The results show that the principal proteins playing a role in schizophrenia can be classified as SCCPs, suggesting that the sensitive cysteine proteome (cysteinet) is defective in this type of psychosis. CONCLUSION: The present review proposes that there is a deregulation of the sensitive cysteine proteome in schizophrenia as the consequence of a functional imbalance among different SCCPs, which play different functions in neurons and glial cells. In this context, the role of NAC to restore and prevent schizophrenic disorders is discussed.

Astroglial Isopotentiality and Calcium-Associated Biomagnetic Field Effects on Cortical Neuronal Coupling.

Synaptic neurotransmission is necessary but does not sufficiently explain superior cognitive faculties. Growing evidence has shown that neuron-astroglial chemical crosstalk plays a critical role in the processing of information, computation, and memory. In addition to chemical and electrical communication among neurons and between neurons and astrocytes, other nonsynaptic mechanisms called ephaptic interactions can contribute to the neuronal synchronization from different brain regions involved in the processing of information. New research on brain astrocytes has clearly shown that the membrane potential of these cells remains very stable among neighboring and distant astrocytes due to the marked bioelectric coupling between them through gap junctions. This finding raises the possibility that the neocortical astroglial network exerts a guiding template modulating the excitability and synchronization of trillions of neurons by astroglial Ca2+-associated bioelectromagnetic interactions. We propose that bioelectric and biomagnetic fields of the astroglial network equalize extracellular local field potentials (LFPs) and associated local magnetic field potentials (LMFPs) in the cortical layers of the brain areas involved in the processing of information, contributing to the adequate and coherent integration of external and internal signals. This article reviews the current knowledge of ephaptic interactions in the cerebral cortex and proposes that the isopotentiality of cortical astrocytes is a prerequisite for the maintenance of the bioelectromagnetic crosstalk between neurons and astrocytes in the neocortex.

Ephaptic Coupling of Cortical Neurons: Possible Contribution of Astroglial Magnetic Fields?

The close anatomical and functional relationship between neuronal circuits and the astroglial network in the neocortex has been demonstrated at several organization levels supporting the idea that neuron-astroglial crosstalk can play a key role in information processing. In addition to chemical and electrical neurotransmission, other non-synaptic mechanisms called ephaptic interactions seem to be important to understand neuronal coupling and cognitive functions. Recent interest in this issue comes from the fact that extra-cranial electric and magnetic field stimulations have shown therapeutic actions in the clinical practice. The present paper reviews the current knowledge regarding the ephaptic effects in mammalian neocortex and proposes that astroglial bio-magnetic fields associated with Ca2+ transients could be implicated in the ephaptic coupling of neurons by a direct magnetic modulation of the intercellular local field potentials.

Cysteinet Dysregulation in Muscular Dystrophies: A Pathogenic Network Susceptible to Therapy.

BACKGROUND: Muscular dystrophies are inherited disorders characterized by progressive skeletal muscle degeneration without curative therapy. The specific defective protein in each type of muscular dystrophy has been associated with different deleterious factors that contribute to the progression of the disease. Among these factors, the impairment of calcium homeostasis, the ubiquitin-proteasome dysfunction, and the oxidative damage of cellular macromolecules seem to be of central importance. Can these different cellular dysfunctions be linked by a common pathogenic mechanism susceptible to therapy? A cellular cysteine network (CYSTEINET) has been proposed previously, as a matrix of interconnected sensitive cysteine-containing proteins (SCCPs) that in addition to reactive species and the cysteine/glutathione cycles can regulate metabolic, redox, and survival cellular pathways by a complex biochemical network of proteins with different functions, but sharing the same regulatory thiol group. OBJECTIVE: Since there are many sensitive cysteine-containing proteins including cysteinedependent enzymes susceptible to redox modifications at cysteine residues that may contribute to muscular degeneration, the aim of this review is to propose that cysteinet dysregulation may explain oxidative damage, calcium disturbances and ubiquitin-proteasome dysfunctions associated with muscular dystrophies. CONCLUSION: The present review proposes that cysteinet dysregulation in muscular dystrophies may represent a common pathogenic network contributing, in association with the specific protein dysfunction, to muscular degeneration. In this context, N-acetylcysteine may have an important role in the restoration of the proposed cysteinet dysregulation associated with these heterogeneous types of diseases.

Cysteine Network (CYSTEINET) Dysregulation in Parkinson's Disease: Role of N-acetylcysteine.

BACKGROUND: Reactive species have been regarded as by-products of cellular metabolism, which cause oxidative damage contributing to aging and neurodegenerative diseases. However, accumulated evidence support the notion that reactive species mediate intracellular and extracellular signals that regulate physiological functions including posttranslational protein modifications. Cysteine thiol groups of proteins are particularly susceptible to oxidative modifications by oxygen, nitrogen and sulfur species generating different products with critical roles in the cellular redox homeostasis. At physiological conditions, reactive species can function not only as intracellular second messengers with regulatory roles in many cellular metabolic processes but also as part of an ancestral biochemical network that controls cellular survival, regeneration, and death. OBJECTIVE: To propose a biochemical network, called cellular cysteine network (CYSTEINET), which can be dysregulated in Parkinson's disease. Due to the fact that there are many cysteine-bearing proteins and cysteine-dependent enzymes susceptible to oxidative modifications, it is proposed that oxidative-changed proteins at cysteine residues may be critical for Parkinson's disease development. CONCLUSION: In the present review, I advance the concept that "cysteinet" is impaired in Parkinson's disease resulting in a functional and structural dysregulation of the matrix of interconnected cysteine-bearing proteins, which in conjunction with reactive species and glutathione regulate the cellular bioenergetic metabolism, the redox homeostasis, and the cellular survival. This network may represent an ancestral down-top system composed of a complex matrix of proteins with very different cellular functions, but bearing the same regulatory thiol radical. Finally, the possible role of N-acetylcysteine and derivatives to regulate "cysteinet" and slow down Parkinson's disease development and progression is discussed.

N-acetyl-cysteine in the treatment of Parkinson's disease. What are we waiting for?

Parkinson's disease is an age-related neurodegenerative disorder that is ameliorated with levodopa. However, long-term use of this drug is limited by motor complications, postural instability and dementia resulting in the progression of the disease. Insights into the organization of the basal ganglia and knowledge of the mechanisms responsible for cell death in Parkinson's disease has permitted the development of putative neuro-protective drugs that might slow the disease progression. Although no drug has yet been established to alter the rate of disease progression, recent publications have confirmed previous results and hypotheses about the probable role of thiolic antioxidants on Parkinson's disease, demonstrating a significant reduction of dopaminergic neuronal degeneration in α-synuclein over expressing mice treated with oral N-acetyl-cysteine. This thiolic antioxidant is a modified form of the natural amino acid cysteine, which is the precursor of the most potent intracellular antioxidant glutathione. Besides, increasing evidence has been accumulated in the last 10years about the beneficial effects of this thiolic antioxidant in experimental and pathologic states of the nervous system, including against neurotoxic substances. The present paper put forward the existing rationale evidence for the use of N-acetyl-cysteine alone or in combination with levodopa in the clinical management of this neurodegenerative disorder.

Magnetic storage of information in the human cerebral cortex: a hypothesis for memory.

The diversity of memory phenomena argues against a single place or anatomical structure for memory in the nervous system. Moreover, molecular mechanisms of information storage and synaptic transmission seem insufficient to support contextual recall and other very complex human memory processes. Here, we propose a new physical model for memory based on the magnetic fields associated with neuronal activity and its possible interaction with the adjacent astroglial network. The hypothesis emphasizes the architectural organization of the human cerebral cortex because the close geometrical relationships between neuronal minicolums and astroglial network acquire transcendental importance.