Identification of peptides interfering with the PP2Ac And LRRK2 interaction.

Transforming growth factor β1-mediated anti-inflammation slows progression of midbrain dopaminergic neurodegeneration in Parkinson's disease?

Parkinson's disease (PD) is a neurodegenerative pathology characterized by the degeneration of midbrain dopamine neurons, whose development and maintenance in brain is related to the transcription factor NR4A2 (also called Nurr1). Notably, NR4A2 is a neuroprotective agent with anti-inflammatory role in microglia and astrocytes. Furthermore, mutations in NR4A2 gene are associated to the familial form of PD, and its gene expression level is down-regulated in blood obtained from PD patients. NR4A2 belongs to the NR4A subfamily consisting of three members: NR4A1, NR4A2, and NR4A3. The NR4A subfamily shares high degree of homology in their molecular structure and cooperates in a spectrum of functions ranging from central nervous system to immune control during physiological and pathological conditions. Considering the close functional link between the member of NR4A subfamily, we performed a gene expression analysis of NR4A1, NR4A2, and NR4A3 in peripheral blood obtained from PD patients and healthy controls (HC). Then, in order to evaluate possible involvement of the NR4A subfamily in other neurodegenerative processes, we carried out the same analysis on blood obtained from Alzheimer's disease (AD) patients. A correlation between clinical features and gene expression was also evaluated. We found a marked down-regulated gene expression of the NR4A subfamily obtained from PD patients, but only a NR4A1 decrease in AD patients compared to HC. This study reports that the entire NR4A subfamily and not only NR4A2 could be systemically involved in PD suggesting that the study of these factors could be a promising approach to develop PD therapy.

2021 Workshop: Neurodegenerative Diseases in the Gut-Brain Axis—Parkinson's Disease

Microorganisms residing in the gut and other anatomical sites exhibit substantial alterations under both physiological and pathological conditions, which are intricately linked to human health. Consequently, the establishment of a comprehensive metagenomic database encompassing diverse body sites under both pathological and physiological conditions is highly important. In this study, we developed BodyMeta (Body Metagenome Database), an upgraded version of the gutMEGA (gut Metagenome Atlas database), and we expanded the included studies considerably from 182 to 1261. These studies were classified into two categories: 600 literature-based studies without raw data (comprising 107 whole-genome sequencing and 493 16S amplicon sequencing studies) and 661 studies containing 663 raw datasets. We systematically categorized 1842 conditions derived from the 1261 studies into 966 pathological and 879 physiological conditions spanning 31 body sites, with the pathological conditions organized according to MeSH (Medical Subject Headings) terms. We comprehensively annotated the microbial contents, diversities, biomarkers and functional differences of the curated raw 16S amplicon sequencing data. In total, 59010 microbial taxa from literature sources and 40657 from raw datasets were mapped to the NCBI Taxonomy database. Additionally, related information about literature and experiments were compiled within BodyMeta. Collectively, the BodyMeta database provides a comprehensive resource for metagenomic investigations related to both physiological and pathological conditions, which can be freely accessed at https://bodymeta.omicsbio.info/.

Parkinson’s disease (PD) is a complex, chronic, and progressive neurodegenerative disease that is characterized by irreversible dopaminergic neuronal loss in the substantia nigra. Alpha-synuclein is normally a synaptic protein that plays a key role in PD due to pathological accumulation as oligomers or fibrils. Clustered alpha-synuclein binds to the Toll-like receptors and activates the microglia, which initiates a process that continues with pro-inflammatory cytokine production and secretion. Pro-inflammatory cytokine overproduction and secretion induce cell death and accelerate PD progression. Microglia are found in a resting state in physiological conditions. Microglia became activated by stimulating Toll-like receptors on it under pathological conditions, such as alpha-synuclein aggregation, environmental toxins, or oxidative stress. The interaction between Toll-like receptors and its downstream pathway triggers an activation series, leads to nuclear factor-kappa B activation, initiates the inflammasome formation, and increases cytokine levels. This consecutive inflammatory process leads to dopaminergic cell damage and cell death. Microglia become overactive in response to chronic inflammation, which is observed in PD and causes excessive cytotoxic factor production, such as reactive oxidase, nitric oxide, and tumor necrosis factor-alpha. This inflammatory process contributes to the exacerbation of pathology by triggering neuronal damage or death. Current treatments, such as dopaminergic agonists, anticholinergics, or monoamine oxidase inhibitors alleviate PD symptoms, but they can not stop the disease progression. Finding a radical treatment option or stopping the progression is essential when considering that PD is the second most reported neurodegenerative disorder. Many cytokines are released during inflammation, and they can start the phagocytic process, which caused the degradation of infected cells along with healthy ones. Therefore, targeting the pathological mechanisms, such as microglial activation, mitochondrial dysfunction, and oxidative stress, that should be involved in the treatment program is important. Neuroinflammation is one of the key factors involved in PD pathogenesis as well as alpha-synuclein accumulation, synaptic dysfunction, or dopaminergic neuronal loss, especially in the substantia nigra. Therefore, evaluating the therapeutic efficiency of the mechanisms is important, such as microglial activation and nuclear factor-kappa B pathway or inflammasome formation inhibition, and cytokine release interruption against neuroinflammation may create new treatment possibilities for PD. This study examined the pathological relation between PD and neuroinflammation, and targeting neuroinflammation as an opportunity for PD treatments, such as Toll-like receptor antagonists, NOD-like receptor family pyrin domain containing-3 inflammasome inhibitors, cytokine inhibitors, peroxisome proliferator-activated receptor-γ agonists, reactive oxygen species inhibitors, and nonsteroidal anti-inflammatory drugs.

Read the full article ‘Beyond the mitochondrion: cytosolic PINK1 remodels dendrites through Protein Kinase A’ on doi: 10.1111/jnc.12494

Rethinking to riluzole mechanism of action: the molecular link among protein kinase CK1δ activity, TDP-43 phosphorylation, and amyotrophic lateral sclerosis pharmacological treatment.

Gut-brain axis and inflammation are two hot topics in Parkinson's disease (PD). In this setting, the leucine-rich repeat kinase 2 (LRRK2) gene, which encodes the eponym protein, has attracted much attention. LRRK2 is not only the gene most commonly associated with Parkinson's disease but also a susceptibility gene for Crohn's disease (CD), thereby suggesting that it may sit at the crossroads of gastrointestinal inflammation, Parkinson's, and Crohn's disease. In contrast to the accumulated data on LRRK2 in the central nervous system (CNS), research on LRRK2 in the digestive tract is still in its infancy, and the scope of the present review article is therefore to review existing studies on LRRK2 in the gastrointestinal tract in both physiological and pathological conditions. In light of current data on LRRK2 in the gastrointestinal tract, we discuss if LRRK2 could be or not regarded as a molecular link between gut inflammation, Parkinson's disease, and Crohn's disease, and we suggest directions for future research.

Among heat shock proteins, mortalin has been linked to the pathogenesis of Parkinson's disease. In the present work a rat model of Parkinson's disease was used to analyze the expression of striatal proteins and, more specifically, mortalin expression. The possible involvement of mortalin in Parkinson's disease pathogenesis was further investigated by utilizing an electrophysiological approach and pharmacological inhibition of mortalin in both the physiological and the parkinsonian states. Proteomic analysis was used to investigate changes in striatal protein expression in the 6-hydroxydopamine rat model of Parkinson's disease. The electrophysiological effects of MKT-077, a rhodamine-123 analogue acting as an inhibitor of mortalin, were measured by field potential recordings from corticostriatal brain slices obtained from control, sham-operated, and 6-hydroxydopamine-denervated animals. Slices in the presence of rotenone, an inhibitor of mitochondrial complex I, were also analyzed. Proteomic analysis revealed downregulation of mortalin in the striata of 6-hydroxydopamine-treated rats in comparison with sham-operated animals. MKT-077 reduced corticostriatal field potential amplitude in physiological conditions, inducing membrane depolarization and inward current in striatal medium spiny neurons. In addition, we observed that concentrations of MKT-077 not inducing any electrophysiological effect in physiological conditions caused significant changes in striatal slices from parkinsonian animals as well as in slices treated with a submaximal concentration of rotenone. These findings suggest a critical link between mortalin function and mitochondrial activity in both physiological and pathological conditions mimicking Parkinson's disease.

The etiology of neurodegenerative diseases is diverse, however most of them share common characteristics: accumulation of misfolded proteins, chronic and sustained neuroinflammation, and the dysfunction and death of certain populations of neurons. The brain of Alzheimer's disease (AD) patients presents amyloid plaques and aggregation of hyperphosphorylated tau. The latter is also present in neurodegenerative tauopathies and in Parkinson's disease (PD). Aggregates of α-synuclein is the characteristic hallmark of PD. In amyotrophic lateral sclerosis (ALS) the mutation of SOD1 promotes its accumulation; and the polyglutamine expansion in huntingtin protein favors its aggregation in Huntington's disease (HD). Thus, the initial proteinopathy could be responsible for triggering the activation of the immunological defenses in the nervous system, as it has been demonstrated in some cases. Microglia and astrocytes are the main glial cells involved in the innate inflammatory response in the central nervous system (CNS). These cells are capable of detecting danger signals, and when activated they secrete inflammatory mediators to try to protect or prevent damage. However, in some cases the inflammatory response becomes sustained by an amplified feedback of release of factors between microglia and astrocytes that further activate these cells. This promotes the recruitment of more glial cells that prolongs and up-regulates the neuroinflammatory response contributing to the progression of the disease (the review of Glass et al. (2010) outlines in detail the contribution of glial cells in neurodegenerative diseases). Neurodegeneration has a remarkable apoptotic component; sustained neuroinflammatory response along with the deregulation of protective mechanisms trigger neuronal death.

This letter describes an interesting case of a 98-year-old woman with multiple head and neck squamous cell carcinoma (HNSCC) and Parkinson disease (PD). The following squamous cell cancers were discovered in this patient: (1) squamous cell carcinoma of the tongue, diagnosed and excised in 2004 with complete clinical recovery; and (2) in situ squamous cell carcinoma of the right cheek and the neck, diagnosed in 2009. She also presented difficulty in the dexterity of the right hand and a typical PD asymmetric presentation. Indeed, the patient had a rest tremor and cogwheel rigidity, bradykinesia bilaterally, stooped posture, turns en bloc, and decreased armswing on the right. These symptoms were responsive to the administration of L-DOPA. It is well known that head and neck cancer is one of the most common worldwide and that tobacco and alcohol consumptions are primary risk factors for HNSCC [1]. On the other hand, PD is one of the most common neurodegenerative disorder with a prevalence of 3% in persons over the age of 65 years [1]. PD is characterized by the presence of intracytoplasmic inclusions, named Lewy bodies (LB), and by a massive loss of dopaminergic neurons in the substantia nigra [2]. Most PD cases are sporadic, but about 15% of them are associated with genetic causes. The loss of dopaminergic afferents from the substantia nigra to the striatum and putamen results in extrapyramidal motor dysfunction, including tremor, rigidity, and bradykinesia. Another hallmark of PD is gliosis, an accumulation of activated microglia and astrocytes in the substantia nigra and striatum [2], although it remains to be clarified how gliosis is initiated and sustained in PD. The symptoms of PD can be ameliorated by medications, such as precursors of dopamines, but these remedies cannot prevent or retard the neurodegenerative progression [3]. Apoptosis is a programmed cell death process under both normal physiological and pathological conditions. Caspases, a family of cysteine-dependent aspartate-specific proteases, are important mediators of the apoptotic process [3]. Caspases cleave numerous intracellular substrates in the initiation of cell dissolution [3, 4]. Caspase 3, apoptosis-related cysteine peptidase (CASP3), maps to human chromosome 4q35 and plays important roles in the extrinsic and intrinsic apoptosis pathways (MIM 600636). Recent molecular epidemiological studies suggest that CASP3 may contribute to HNSCC susceptibility and disease progression and that increased CASP3 expression is associated with tumors of the mouth [5]. Moreover, previous studies suggested that CASP3 activation and subsequent apoptosis of dopamine neurons in the substantia nigra may be the initial step essential for the development of PD [6]. The poly (ADP-ribose) polymerase 1 (PARP1) gene, located at 1q42, is 43 Kb long and splits into 23 exons A. E. Calogero M. C. Giuffrida D. Giuffrida S. La Vignera R. Castiglione M. Salemi Section of Endocrinology, Andrology and Internal Medicine, Department of Internal Medicine and Systemic Diseases, University of Catania, Catania, Italy

Aberrant Protein S-Nitrosylation in Neurodegenerative Diseases

Angiogenesis depends on proangiogenic and anti-angiogenic molecules that regulate endothelial cell proliferation and migration. Well-regulated angiogenesis plays a pivotal role in many physiological conditions such as reproduction and embryonic development, while abnormal angiogenesis is also the basis of a variety of pathological processes including tumor metastasis and atherosclerotic plaque formation. Melatonin has a variety of biological effects, including inhibition of tumor metastasis, stabilizing atherosclerotic plaques, and the regulation of seasonal reproductive rhythms, etc. During certain pathophysiological processes, melatonin exerts different functions depending on its ability to regulate angiogenesis. This review reveals that melatonin has different effects on neovascularization under different physiological and pathological conditions. In tumors, in age-related ocular diseases, and in a hypoxic environment, melatonin inhibits neovascularization in tissues, while in gastric ulcers, skin lesions, and some physiologic processes, it promotes angiogenesis. We also speculate that melatonin may inhibit the neovascularization in atherosclerotic plaques, thus preventing the initiation and development of atherosclerosis. Most studies suggest that these effects are related to the role of melatonin in regulating of vascular endothelial growth factor and its receptors, but the specific regulatory mechanisms remain disparate, which may lead to the differential effects of melatonin on angiogenesis under different conditions. In this review, we thus summarize some seemingly contradictory mechanisms by which melatonin controls angiogenesis under different pathological and physiological conditions, and urge that the regulatory mechanisms be further studied.

α-Synuclein (αS) is a protein with multiple conformations and interactions. Natively unfolded in solution, αS accumulates as amyloid in neurological tissue in Parkinson disease and interacts with membranes under both physiological and pathological conditions. Here, we used cryoelectron microscopy in conjunction with electron paramagnetic resonance (EPR) and other techniques to characterize the ability of αS to remodel vesicles. At molar ratios of 1:5 to 1:40 for protein/lipid (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol), large spherical vesicles are converted into cylindrical micelles ~50 Å in diameter. Other lipids of the same charge (negative) exhibit generally similar behavior, although bilayer tubes of 150-500 Å in width are also produced, depending on the lipid acyl chains. At higher protein/lipid ratios, discoid particles, 70-100 Å across, are formed. EPR data show that, on cylindrical micelles, αS adopts an extended amphipathic α-helical conformation, with its long axis aligned with the tube axis. The observed geometrical relationship between αS and the micelle suggests that the wedging of its long α-helix into the outer leaflet of a membrane may cause curvature and an anisotropic partition of lipids, leading to tube formation.

Neuroprotective effects of vascular endothelial growth factor A in the experimental autoimmune encephalomyelitis model of multiple sclerosis