A Copper-Selective Sensor and Its Inhibition of Copper-Amyloid Beta Aggregation.

Copper is an essential trace metal for biological processes in humans and animals. A low level of copper detection at physiological pH using fluorescent probes is very important for in vitro applications, such as the detection of copper in water or urine, and in vivo applications, such as tracking the dynamic copper concentrations inside cells. Copper homeostasis is disrupted in neurological diseases like Alzheimer's disease, and copper forms aggregates with amyloid beta (Ab42) peptide, resulting in senile plaques in Alzheimer's brains. Therefore, a selective copper detector probe that can detect amyloid beta peptide-copper aggregates and decrease the aggregate size has potential uses in medicine. We have developed a series of Cu2+-selective low fluorescent to high fluorescent tri and tetradentate dentate ligands and conjugated them with a peptide ligand to amyloid-beta binding peptide to increase the solubility of the compounds and make the resultant compounds bind to Cu2+-amyloid aggregates. The copper selective compounds were developed using chemical scaffolds known to have high affinity and selectivity for Cu2+, and their conjugates with peptides were tested for affinity and selectivity towards Cu2+. The test results were used to inform further improvement of the next compound. The final Cu2+ chelator-peptide conjugate we developed showed high selectivity for Cu2+ and high fluorescence properties. The compound bound 1:1 to Cu2+ ion, as determined from its Job's plot. Fluorescence of the ligand could be detected at nanomolar concentrations. The effect of this ligand on controlling Cu2+-Ab42 aggregation was studied using fluorescence assays and microscopy. It was found that the Cu2+-chelator-peptide conjugate efficiently reduced aggregate size and, therefore, acted as an inhibitor of Ab42-Cu2+ aggregation. Since high micromolar concentrations of Cu2+ are present in senile plaques, and Cu2+ accelerates the formation of toxic soluble aggregates of Ab42, which are precursors of insoluble plaques, the developed hybrid molecule can potentially serve as a therapeutic for Alzheimer's disease.

Role of Amyloidogenic and Non-Amyloidogenic Protein Spaces in Neurodegenerative Diseases and their Mitigation Using Theranostic Agents.

Neurodegenerative diseases (NDDs) refer to a complex heterogeneous group of diseases which are associated with the accumulation of amyloid fibrils or plaques in the brain leading to progressive loss of neuronal functions. Alzheimer's disease is one of the major NDD responsible for 60-80 % of all dementia cases. Currently, there are no curative or disease-reversing/modifying molecules for many of the NDDs except a few such as donepezil, rivastigmine, galantamine, carbidopa and levodopa which treat the disease-associated symptoms. Similarly, there are very few FDA-approved tracers such as flortaucipir (Tauvid) for tau fibril imaging and florbetaben (Neuraceq), flutemetamol (Vizamyl), and florbetapir (Amyvid) for amyloid imaging available for diagnosis. Recent advances in the cryogenic electron microscopy reported distinctly different microstructures for tau fibrils associated with different tauopathies highlighting the possibility to develop tauopathy-specific imaging agents and therapeutics. In addition, it is important to identify the proteins that are associated with disease development and progression to know about their 3D structure to develop various diagnostics, therapeutics and theranostic agents. The current article discusses in detail the disease-associated amyloid and non-amyloid proteins along with their structural insights. We comprehensively discussed various novel proteins associated with NDDs and their implications in disease pathology. In addition, we document various emerging chemical compounds developed for diagnosis and therapy of different NDDs with special emphasis on theranostic agents for better management of NDDs.

Structural packing of the non-amyloid component core domain in α-synuclein plays a role in the stability of the fibrils.

Parkinson's disease (PD) is one of many neurodegenerative diseases. The protein associated with PD is α-synuclein (AS). Aggregation of AS protein into oligomers, protofilaments, and finally to fibrils yields to the development of PD. The aggregation process of AS leads to the formation of polymorphic AS fibrils. Herein, we compared four polymorphic full-length AS1-140 fibrils, using extensive computational tools. The main conclusion of this study emphasizes the role of the structurally packed non-amyloid component (NAC) core domain in AS fibrils. Polymorphic AS fibrils that presented a packed NAC core domain, exhibited more ß-sheets and fewer fluctuations in the NAC domain. Hence, these AS fibrils are more stable and populated than the AS fibrils, by which the NAC domains are more exposed, more fluctuate and less packed in the fibrillary structure. Therefore, this study emphasizes the importance of the NAC domain packing in the morphology of AS fibrils. The results obtained in this study will initiate future studies to develop compounds to prevent and inhibit AS aggregation.

Renal involvement in monogenic autoinflammatory diseases: A narrative review.

Autoinflammatory diseases (AIDs) are mostly caused by dysfunctions in single genes encoding for proteins with a prominent role in the regulation of innate immunity, such as complement factors, inflammasome components, tumour necrosis factor (TNF)-α, and proteins belonging to type I-interferon (IFN) signalling pathways. Due to the deposition of amyloid A (AA) fibrils in the glomeruli, unprovoked inflammation in AIDs frequently affects renal health. In fact, secondary AA amyloidosis is the most common form of amyloidosis in children. It is caused by the extracellular deposition of fibrillar low-molecular weight protein subunits resulting from the degradation and accumulation of serum amyloid A (SAA) in numerous tissues and organs, primarily the kidneys. The molecular mechanisms underlying AA amyloidosis in AIDs are the elevated levels of SAA, produced by the liver in response to pro-inflammatory cytokines, and a genetic predisposition due to specific SAA isoforms. Despite the prevalence of amyloid kidney disease, non-amyloid kidney diseases may also be responsible for chronic renal damage in children with AIDs, albeit with distinct characteristics. Glomerular damage can result in various forms of glomerulonephritis with distinct histologic characteristics and a different underlying pathophysiology. This review aims to describe the potential renal implications in patients with inflammasomopathies, type-I interferonopathies, and other rare AIDs in an effort to improve the clinical course and quality of life in paediatric patients with renal involvement.

Shapeshifter TDP-43: Molecular mechanism of structural polymorphism, aggregation, phase separation and their modulators.

TDP-43 is a nucleic acid-binding protein that performs physiologically essential functions and is known to undergo phase separation and aggregation during stress. Initial observations have shown that TDP-43 forms heterogeneous assemblies, including monomer, dimer, oligomers, aggregates, phase-separated assemblies, etc. However, the significance of each assembly of TDP-43 concerning its function, phase separation, and aggregation is poorly known. Furthermore, how different assemblies of TDP-43 are related to each other is unclear. In this review, we focus on the various assemblies of TDP-43 and discuss the plausible origin of the structural heterogeneity of TDP-43. TDP-43 is involved in multiple physiological processes like phase separation, aggregation, prion-like seeding, and performing physiological functions. However, the molecular mechanism behind the physiological process performed by TDP-43 is not well understood. The current review discusses the plausible molecular mechanism of phase separation, aggregation, and prion-like propagation of TDP-43.

Fibrillary Glomerulonephritis: A Great Mimicker of Rapidly Progressive Glomerulonephritis.

Fibrillary glomerulonephritis (FGN) is a rare but severe kidney disease found to have non-amyloid fibrillary deposits in the mesangium and/or glomerular capillary wall. It was initially thought to be idiopathic, but recent studies show an association with autoimmune disease, malignancy, and hepatitis C infection. We report a case of a non-diabetic patient presenting with long-standing microscopic hematuria, progressive proteinuria, hypertension, and worsening kidney function. The kidney biopsy demonstrated subepithelial fibrillar deposits of size 17 mm randomly oriented with one partial cellular crescent on electron microscopy. Direct immunofluorescence showed no staining for IgG or light chains. It was weakly positive for Congo red staining with a slightly higher serum free kappa/lambda light chain ratio, but serum immunofixation showed no monoclonal protein detection. We empirically treated with rituximab but with no clear benefit or no renal recovery and eventually started on hemodialysis. FGN has an extremely poor prognosis with very few treatment options available. We report this case to emphasize the need for larger, multi-center studies for treatment approaches with collaborating and consolidating data from case reports and case series due to the rarity of the disease.

Aluminum inhibits non-amyloid pathways via retinoic acid receptor.

BACKGROUND: Aluminium neurotoxicity has been widely confirmed and mainly manifests as cognitive impairment. Al3+ can inhibit the expression of ADAM10, a key enzyme of the nonamyloid pathway, but its mechanism of toxicity has not been fully elucidated. Studies have shown that RARs can regulate ADAM10 expression. METHODS: We explored whether Al3+ affects the expression of ADAM10 through RARs, thereby affecting the nonamyloid pathway. RESULTS: Al3+ reduced the expressions of RARα, RARß and ADAM10. The expression levels of the RARα, RARß and ADAM10 proteins were upregulated in the RA group compared with the control group. In the RA + 200 µmol Al(mal)3 group, the downregulation of RARα, RARß and ADAM10 was weaker than that of the 200 µmol Al(mal)3 group, which indicated that RA participated in and upregulated the expression of ADAM10 through RARα and RARß. CONCLUSION: Al3+ inhibits ADAM10 expression through RARα and RARß and results in a decrease in the nonamyloid pathway.

Nutcracker syndrome: a potentially underdiagnosed cause of proteinuria in children with familial Mediterranean fever.

INTRODUCTION: Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory disease with an increased risk for secondary amyloidosis. Since lifelong colchicine has been the treatment of choice that prevents renal amyloidosis, non-amyloid kidney diseases are more frequently considered in the differential diagnosis of proteinuria. Nutcracker syndrome (NCS) can be one of the confounding causes. This long-term retrospective study aimed to evaluate the causes of proteinuria in a pediatric cohort of patients with FMF and discuss changing trends in recent years . METHODS: Demographic, clinic, and laboratory data were extracted from electronic medical records of patients with FMF. All urine tests of the study population were reviewed. Patients were evaluated for persistent proteinuria and grouped according to the etiology of proteinuria. RESULTS: A total of 576 patients with FMF were identified with a mean follow-up of 6.3 years in the last 10 years; 8% had persistent proteinuria. The etiology was NCS in 67.5% of the patients with proteinuria, and renal amyloidosis was less commonly encountered (15%) without any new diagnosis for the last 8 years. Non-amyloid kidney diseases were also diagnosed in 17.5% of the patients. Patients with NCS had significantly lower BMI than other patients in the cohort and less subclinical inflammation, higher hemoglobin concentration, and milder levels of proteinuria with normal serum albumin and eGFR than other patients with proteinuria. CONCLUSION: Nutcracker syndrome is the leading cause of proteinuria in children with FMF nowadays, and it should be kept in mind during the evaluation of proteinuria in these patients. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinicopathological Assessment of Kidney Biopsies in Children with Familial Mediterranean Fever: A Single-Center Experience.

OBJECTIVES: Familial Mediterranean fever (FMF) is a monogenic auto-inflammatory disease which might rarely cause glomerulopathy in patients. The aim of this study was to determine the clinical, demographic, and genetic characteristics and type of glomerular lesions in pediatric FMF patients who underwent kidney biopsy. METHODS: The data of 30 pediatric FMF patients with biopsy-proven glomerulopathy were retrospectively reviewed. Patients were grouped into 2 categories as amyloid nephropathy (AN, n = 16) and non-amyloid nephropathy (N-AN, n = 14). RESULTS: The mean age at FMF diagnosis was 7.2 ± 3.0 years. The AN group showed higher rates of hypertension, higher levels of 24-h protein excretion and serum creatinine, and lower estimated glomerular filtration rate at the time of kidney biopsy. The rate of ESRD was found to be higher in the AN group (p = 0.011). Mesangioproliferative glomerulonephritis was the most common pathology in the N-AN group (21.4%). The frequency of amyloidosis was significantly higher in patients with homozygous p.M694V mutations than non-homozygous p.M694V mutations (p = 0.039). CONCLUSIONS: In children with FMF, nephropathy is rare. To our knowledge, this is the first study performed in pediatric FMF patients exploring amyloid and non-amyloid glomerulopathies. Patients with AN had higher rates of proteinuria, lower estimated glomerular filtration rate levels, and higher blood pressure than N-AN patients at the time of biopsy.

A Non-amyloid Prion Particle that Activates a Heritable Gene Expression Program.

Spatiotemporal gene regulation is often driven by RNA-binding proteins that harbor long intrinsically disordered regions in addition to folded RNA-binding domains. We report that the disordered region of the evolutionarily ancient developmental regulator Vts1/Smaug drives self-assembly into gel-like condensates. These proteinaceous particles are not composed of amyloid, yet they are infectious, allowing them to act as a protein-based epigenetic element: a prion [SMAUG+]. In contrast to many amyloid prions, condensation of Vts1 enhances its function in mRNA decay, and its self-assembly properties are conserved over large evolutionary distances. Yeast cells harboring [SMAUG+] downregulate a coherent network of mRNAs and exhibit improved growth under nutrient limitation. Vts1 condensates formed from purified protein can transform naive cells to acquire [SMAUG+]. Our data establish that non-amyloid self-assembly of RNA-binding proteins can drive a form of epigenetics beyond the chromosome, instilling adaptive gene expression programs that are heritable over long biological timescales.

[A case of bronchiectasis due to light chain deposition disease]. / Histoire naturelle d'une forme bronchectasiante de la maladie à dépôts de chaînes légères.

INTRODUCTION: The natural history of orphan lung diseases is often unclear. We report the long-term follow-up of a case of bronchiectasis due to pulmonary non amyloid light chain deposition disease (LCDD). CASE REPORT: A 50-year-old woman who was a smoker, was diagnosed with diffuse thin walled bronchiectasis of uncertain origin after presenting with a respiratory tract infection. Ten years later, the combination of bronchiectasis, the appearance of pulmonary cysts and the identification of increased kappa free light chains evoked the diagnosis of pulmonary LCDD. The diagnosis was confirmed by lung biopsy. No immunoproliferative disorder was identified. During the 12 years follow-up, dyspnea worsened progressively and bronchiectasis and lung cysts extended leading to multicystic lung disease. Pulmonary function tests did not show any ventilatory defect but a small decrease in carbon monoxide transfer factor occurred. CONCLUSION: We describe the evolution of a rare presentation of isolated pulmonary LCDD, characterized by cystic diffuse atypical bronchiectasis with thin walls, associated with progressive cystic destruction of the lung parenchyma. The possibility of pulmonary LCDD should be considered in cases of atypical bronchiectasis of unknown etiology.

Fibrillary Glomerulonephritis in a Patient with Sjogren's Syndrome.

Fibrillary glomerulonephritis (FGN) is an uncommon cause of primary glomerular disease. FGN is usually idiopathic; however, it has been associated with underlying malignancy or autoimmune diseases in some patients as well. The most commonly found autoimmune diseases in FGN patients include Graves' disease, systemic lupus nephritis, Chron's disease, and idiopathic thrombocytopenia purpura. FGN in a patient with underlying asymptomatic Sjogren's syndrome is very rare in the literature, with only two previously reported cases of this association. We present the case of a 75-year-old female with a past medical history of asymptomatic primary Sjogren's syndrome and fibromyalgia, who presented to emergency department with a new episode of hypertension. The electron microscopy (EM) showed randomly arranged nonamyloid fibrillar deposits in the mesangium and glomerular capillary walls, confirming FGN. In this case-based review, we describe in detail the diagnostic work-up, clinical course, and complications in management. We also discuss some of the other nonamyloid fibrillary glomerular diseases.

The status of glycation in protein aggregation.

Protein crucial function and flexibility directly depend on its whole structure which is determined by the native distribution of structural elements. Any disturbances in a protein architecture leads to many kind of abnormalities and intra- or extracellular accumulation of misfolded proteins which are the basis of conformational diseases. Glycation is one of the most important unwanted post-translational modifications (PTM) which modifies protein three dimensional decoration and triggers its abnormalities. In current review, we take a look at the brief history of protein glycation, its mechanism and kinetics, glycation consequences and toxic products and its involvement in protein chemical modification, aggregation amyloids and fibril formation and different mechanisms induced by such alterations.

PAS-positive extracellular deposits within germinal centers of hyperplastic follicles during SIV infection in a rhesus macaque.

BACKGROUND: Lymphoid tissue remodeling is characteristic of chronic simian immunodeficiency virus infection. METHODS: A rhesus macaque infected with SIVmac239 was necropsied and its lymphoid tissues subjected to histopathology characterization. RESULTS: Germinal centers in spleen and lymph nodes contained PAS-positive, non-amyloid extracellular deposits, decreased T follicular helper cells, and normal density of Ki67(+) B cells. CONCLUSIONS: A possible mechanism for PAS-positive deposits includes exaggerated involution of SIV-induced follicular hyperplasia secondary to virus-associated immune reaction.

[An unusual cause of cystic lung disease: light chain deposition disease]. / Une cause rare de maladie kystique pulmonaire: maladie à dépôts de chaînes légères d'immunoglobuline.

INTRODUCTION: Light chain deposition disease is a rare clinical entity characterized by deposition of monoclonal immunoglobulin light chains in organs. The kidneys are almost always affected, while the lung manifestations that have been reported, including nodular or diffuse disease, especially cystic lesions, are unusual. CASE REPORT: We report the case of a 60-year-old man with a diffuse infiltrative lung disease characterized by numerous apical cysts. The diagnosis of light chain deposition cystic lung disease was obtained by surgical lung biopsy. Light chain deposits in the salivary glands were the only extrapulmonary manifestation. Despite 12 chemotherapy cycles, the patient's lung function and radiological appearances worsened. CONCLUSION: This is the fourth case describing a cystic lung disease due to light chain deposition in the literature. It highlights the need for comprehensive investigations so as not to miss this rare cause of cystic lung disease, which appears to be related to a primary pulmonary lymphoproliferative disorder. The only treatment that appears to be effective is lung transplantation.