Pathogenic Impact of α-Synuclein Phosphorylation and Its Kinases in α-Synucleinopathies

α-Synuclein is a protein with a molecular weight of 14.5 kDa and consists of 140 amino acids encoded by the SNCA gene. Missense mutations and gene duplications in the SNCA gene cause hereditary Parkinson’s disease. Highly phosphorylated and abnormally aggregated α-synuclein is a major component of Lewy bodies found in neuronal cells of patients with sporadic Parkinson’s disease, dementia with Lewy bodies, and glial cytoplasmic inclusion bodies in oligodendrocytes with multiple system atrophy. Aggregated α-synuclein is cytotoxic and plays a central role in the pathogenesis of the above-mentioned synucleinopathies. In a healthy brain, most α-synuclein is unphosphorylated; however, more than 90% of abnormally aggregated α-synuclein in Lewy bodies of patients with Parkinson’s disease is phosphorylated at Ser129, which is presumed to be of pathological significance. Several kinases catalyze Ser129 phosphorylation, but the role of phosphorylation enzymes in disease pathogenesis and their relationship to cellular toxicity from phosphorylation are not fully understood in α-synucleinopathy. Consequently, this review focuses on the pathogenic impact of α-synuclein phosphorylation and its kinases during the neurodegeneration process in α-synucleinopathy.     

Muscle Wasting in Chronic Kidney Disease: Mechanism and Clinical Implications—A Narrative Review

Muscle wasting, known to develop in patients with chronic kidney disease (CKD), is a deleterious consequence of numerous complications associated with deteriorated renal function. Muscle wasting in CKD mainly involves dysregulated muscle protein metabolism and impaired muscle cell regeneration. In this narrative review, we discuss the cardinal role of the insulin-like growth factor 1 and myostatin signaling pathways, which have been extensively investigated using animal and human studies, as well as the emerging concepts in microRNA- and gut microbiota-mediated regulation of muscle mass and myogenesis. To ameliorate muscle loss, therapeutic strategies, including nutritional support, exercise programs, pharmacological interventions, and physical modalities, are being increasingly developed based on advances in understanding its underlying pathophysiology.     

Novel Cyclopentaquinoline and Acridine Analogs as Multifunctional,Potent Drug Candidates in Alzheimer’s Disease

A series of new cyclopentaquinoline derivatives with 9-acridinecarboxylic acid and a different alkyl chain length were synthesized, and their ability to inhibit cholinesterases was evaluated. All designed compounds, except derivative 3f, exhibited a selectivity for butyrylcholinesterase (BuChE) with IC₅₀ values ranging from 103 to 539 nM. The 3b derivative revealed the highest inhibitory activity towards BuChE (IC₅₀ = 103.73 nM) and a suitable activity against AChE (IC₅₀ = 272.33 nM). The 3f derivative was the most active compound to AChE (IC₅₀ = 113.34 nM) with satisfactory activity towards BuChE (IC₅₀ = 203.52 nM). The potential hepatotoxic effect was evaluated for both 3b and 3f compounds. The 3b and 3f potential antioxidant activity was measured using the ORAC-FL method. The 3b and 3f derivatives revealed a significantly higher antioxidant potency, respectively 35 and 25 higher than tacrine. Theoretical, physicochemical, and pharmacokinetic properties were calculated using ACD Labs Percepta software. Molecular modeling and kinetic study were used to reveal the mechanism of cholinesterase inhibition in the most potent compounds: 3b and 3f.     

Mitochondrial Dysfunction in Spinocerebellar Ataxia Type 3 Is Linked to VDAC1 Deubiquitination

Dysfunctional mitochondria are linked to several neurodegenerative diseases. Metabolic defects, a symptom which can result from dysfunctional mitochondria, are also present in spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, the most frequent, dominantly inherited neurodegenerative ataxia worldwide. Mitochondrial dysfunction has been reported for several neurodegenerative disorders and ataxin-3 is known to deubiquitinylate parkin, a key protein required for canonical mitophagy. In this study, we analyzed mitochondrial function and mitophagy in a patient-derived SCA3 cell model. Human fibroblast lines isolated from SCA3 patients were immortalized and characterized. SCA3 patient fibroblasts revealed circular, ring-shaped mitochondria and featured reduced OXPHOS complexes, ATP production and cell viability. We show that wildtype ataxin-3 deubiquitinates VDAC1 (voltage-dependent anion channel 1), a member of the mitochondrial permeability transition pore and a parkin substrate. In SCA3 patients, VDAC1 deubiquitination and parkin recruitment to the depolarized mitochondria is inhibited. Increased p62-linked mitophagy, autophagosome formation and autophagy is observed under disease conditions, which is in line with mitochondrial fission. SCA3 fibroblast lines demonstrated a mitochondrial phenotype and dysregulation of parkin-VDAC1-mediated mitophagy, thereby promoting mitochondrial quality control via alternative pathways.     

Alpha-Synuclein Autoimmune Decline in Prodromal Multiple System Atrophy and Parkinson’s Disease

Multiple-system trophy (MSA) and Parkinson’s Disease (PD) are both progressive, neurodegenerative diseases characterized by neuropathological deposition of aggregated alpha-synuclein (αSyn). The causes behind this aggregation are still unknown. We have reported aberrancies in MSA and PD patients in naturally occurring autoantibodies (nAbs) against αSyn (anti-αSyn-nAbs), which are important partakers in anti-aggregatory processes, immune-mediated clearance, and anti-inflammatory functions. To elaborate further on the timeline of autoimmune aberrancies towards αSyn, we investigated here the Immunoglobulin (Ig) affinity profile and subclass composition (IgG-total, IgG1-4 and IgM) of anti-αSyn-nAbs in serum samples from prodromal (p) phases of MSA and PD. Using an electrochemiluminescence competition immunoassay, we confirmed that the repertoire of high-affinity anti-αSyn-nAbs is significantly reduced in pMSA and pPD. Further, we demonstrated that pPD had increased anti-αSyn IgG-total levels compared to pMSA and controls, concordant with increased anti-αSyn IgG1 levels in pPD. Anti-αSyn IgG2 and IgG4 levels were reduced in pMSA and pPD compared with controls, whereas anti-αSyn IgG3 levels were reduced in pMSA compared to pPD and controls. The results indicate that the impaired reactivity towards αSyn occurs prior to disease onset. The apparent lack of high-affinity anti-αSyn nAbs may result in reduced clearance of αSyn, leading to aggregation of the protein. Thus, this study provides novel insights into possible causes behind the pathogenesis in synucleinopathies such as MSA and PD.     

Roles of AGD2a in Plant Development and Microbial Interactions of Lotus japonicus

Arabidopsis AGD2 (Aberrant Growth and Death2) and its close homolog ALD1 (AGD2-like defense response protein 1) have divergent roles in plant defense. We previously reported that modulation of salicylic acid (SA) contents by ALD1 affects numbers of nodules produced by Lotus japonicus, but AGD2′s role in leguminous plants remains unclear. A combination of enzymatic analysis and biological characterization of genetic materials was used to study the function of AGD2 (LjAGD2a and LjAGD2b) in L. japonicus. Both LjAGD2a and LjAGD2b could complement dapD and dapE mutants of Escherichia coli and had aminotransferase activity in vitro. ljagd2 plants, with insertional mutations of LjAGD2, had delayed flowering times and reduced seed weights. In contrast, overexpression of LjAGD2a in L. japonicus induced early flowering, with increases in seed and flower sizes, but reductions in pollen fertility and seed setting rates. Additionally, ljagd2a mutation resulted in increased expression of nodulin genes and corresponding increases in infection threads and nodule numbers following inoculation with Rhizobium. Changes in expression of LjAGD2a in L. japonicus also affected endogenous SA contents and hence resistance to pathogens. Our results indicate that LjAGD2a functions as an LL-DAP aminotransferase and plays important roles in plant development. Moreover, LjAGD2a activates defense signaling via the Lys synthesis pathway, thereby participating in legume–microbe interaction.     

Chronic Hyperkaliemia in Chronic Kidney Disease: An Old Concern with New Answers

Increasing potassium intake ameliorates blood pressure (BP) and cardiovascular (CV) prognoses in the general population; therefore the World Health Organization recommends a high-potassium diet (90–120 mEq/day). Hyperkalaemia is a rare condition in healthy individuals due to the ability of the kidneys to effectively excrete dietary potassium load in urine, while an increase in serum K⁺ is prevalent in patients with chronic kidney disease (CKD). Hyperkalaemia prevalence increases in more advanced CKD stages, and is associated with a poor prognosis. This scenario generates controversy on the correct nutritional approach to hyperkalaemia in CKD patients, considering the unproven link between potassium intake and serum K⁺ levels. Another concern is that drug-induced hyperkalaemia leads to the down-titration or withdrawal of renin-angiotensin system inhibitors (RASI) and mineralocorticoids receptors antagonists (MRA) in patients with CKD, depriving these patients of central therapeutic interventions aimed at delaying CKD progression and decreasing CV mortality. The new K⁺-binder drugs (Patiromer and Sodium-Zirconium Cyclosilicate) have proven to be adequate and safe therapeutic options to control serum K⁺ in CKD patients, enabling RASI and MRA therapy, and possibly, a more liberal intake of fruit and vegetables.     

The Role of Autophagy and Pyroptosis in Liver Disorders

Pyroptosis is a programmed cell death caused by inflammasomes, which can detect cell cytosolic contamination or disturbance. In pyroptosis, caspase-1 or caspase-11/4/5 is activated, cleaving gasdermin D to separate its N-terminal pore-forming domain (PFD). The oligomerization of PFD forms macropores in the membrane, resulting in swelling and membrane rupture. According to the different mechanisms, pyroptosis can be divided into three types: canonical pathway-mediated pyroptosis, non-canonical pathway-mediated pyroptosis, and caspase-3-induced pyroptosis. Pyroptosis has been reported to play an important role in many tissues and organs, including the liver. Autophagy is a highly conserved process of the eukaryotic cell cycle. It plays an important role in cell survival and maintenance by degrading organelles, proteins and macromolecules in the cytoplasm. Therefore, the dysfunction of this process is involved in a variety of pathological processes. In recent years, autophagy and pyroptosis and their interactions have been proven to play an important role in various physiological and pathological processes, and have gradually attracted more and more attention to become a research hotspot. Therefore, this review summarized the role of autophagy and pyroptosis in liver disorders, and analyzed the related mechanism to provide a basis for future research.     

Enhancing the Therapeutic Potential of Mesenchymal Stromal Cell-Based Therapies with an Anti-Fibrotic Agent for the Treatment of Chronic Kidney Disease

Chronic kidney disease (CKD) affects 1 in 10 members of the general population, placing these patients at an increasingly high risk of kidney failure. Despite the significant burden of CKD on various healthcare systems, there are no effective cures that reverse or even halt its progression. In recent years, human bone-marrow-derived mesenchymal stromal cells (BM-MSCs) have been recognised as a novel therapy for CKDs, owing to their well-established immunomodulatory and tissue-reparative properties in preclinical settings, and their promising safety profile that has been demonstrated in patients with CKDs from several clinical trials. However, renal fibrosis (scarring), a hallmark of CKD, has been shown to impair the viability and functionality of BM-MSCs post-transplantation. This has suggested that BM-MSCs might require a pre-treatment or adjunct therapy that can enhance the viability and therapeutic efficacy of these stromal cells in chronic disease settings. To address this, recent studies that have combined BM-MSCs with the anti-fibrotic drug serelaxin (RLX), have demonstrated the enhanced therapeutic potential of this combination therapy in normotensive and hypertensive preclinical models of CKD. In this review, a critical appraisal of the preclinical data available on the anti-fibrotic and renoprotective actions of BM-MSCs or RLX alone and when combined, as a treatment option for normotensive vs. hypertensive CKD, is discussed.