XCT 790 is a pharmacological aggrephagy inducer in a yeast model of proteotoxicity.

Aggrephagy is a selective autophagic degradation intracellular mechanism that clears toxic misfolded protein aggregates such as α-synuclein. Here, we identify and demonstrate that the small molecule, XCT 790 alleviates α-synuclein-mediated adverse effects in a yeast model of proteotoxicity. XCT 790 induced general autophagy and also enhanced starvation-induced autophagy. Mechanistically, we showed that XCT 790 clears toxic α-synuclein aggregates in an autophagy-dependent manner. Interestingly, XCT 790 did not demonstrate a synergistic effect on autophagy induction in the presence of another autophagy inducer such as 6-Bio.

Soluble 4R0N Tau Abrogates Endocytic Vesicular Dynamics.

Aggregated tau is a hallmark neuropathological feature in numerous neurodegenerative disorders. Previous studies aiming to validate aggregated tau pathology as a pathogenic driver of neurodegeneration in correlation to characteristic behavioral phenotypes have had shortcomings. Although studies on soluble tau pathology have effectively addressed these shortcomings, the role of soluble tau in the molecular pathogenesis of neurodegeneration is not yet unequivocally established. In sporadic Alzheimer's disease (AD), the relevance of soluble tau pathology in endolysosomal dysfunction and autophagic stress, some of the earliest disease manifestations, is unclear. In this study, we report that soluble 4R0N tau overexpression affects the expression levels of certain markers associated with the endolysosomal system and autophagy. Moreover, through live-cell imaging, we found that the vesicular dynamics of early endosomes were affected with respect to spatiotemporal parameters and vesicle maturation. Additionally, we observed the localization of amyloid precursor protein (APP) along the endocytic pathway and found that upon overexpression of soluble 4R0N tau, APP was preferentially localized to the endocytic compartments implicated in the amyloidogenic pathway. Overall, our observations indicate that soluble 4R0N tau abrogates the dynamics of the endolysosomal system, autophagy, and affects the trafficking of APP. Since the amyloidogenic processing of APP occurs during its progression through the endocytic pathway, our results suggest that the generation of amyloid-ß (Aß) might also be modulated.

Pharmacological Tools to Modulate Autophagy in Neurodegenerative Diseases.

Considerable evidences suggest a link between autophagy dysfunction, protein aggregation, and neurodegenerative diseases. Given that autophagy is a conserved intracellular housekeeping process, modulation of autophagy flux in various model organisms have highlighted its importance for maintaining proteostasis. In postmitotic cells such as neurons, compromised autophagy is sufficient to cause accumulation of ubiquitinated aggregates, neuronal dysfunction, degeneration, and loss of motor coordination-all hallmarks of neurodegenerative diseases. Reciprocally, enhanced autophagy flux augments cellular and organismal health, in addition to extending life span. These genetic studies not-withstanding a plethora of small molecule modulators of autophagy flux have been reported that alleviate disease symptoms in models of neurodegenerative diseases. This review summarizes the potential of such molecules to be, perhaps, one of the first autophagy drugs for treating these currently incurable diseases.

Nucleolus: A Protein Quality Control Compartment.

Frottin et al. uncovered a role for the nucleolus as a key quality control compartment that regulates misfolded nuclear proteins. This nonmembrane compartment achieves this by forming liquid-like protein condensates that aid protein refolding in a heat-shock protein (Hsp)70-dependent manner. This liquid-liquid phase separation (LLPS)-mediated nuclear quality control mechanism is perturbed during neurodegeneration.

A small molecule autophagy inducer exerts cytoprotection against α-synuclein toxicity.

α-synucleopathies are protein-misfolding disorders occur primarily due to aggregation and toxicity of α-synuclein. This study characterized the small molecule AGK2 as a modifier of α-synuclein mediated toxicity in an autophagy dependent manner in both yeast and mammalian cell line models. In yeast system, AGK2 enhances autophagy to clear toxic α-synuclein aggregates in an autophagy dependent manner. Autophagy flux analyses revealed that AGK2 induces autophagy especially autolysosomes. Importantly, AGK2 induces autophagy in an mTOR independent manner. These features enable AGK2 to exert cytoprotective potential against α-synuclein mediated toxicity in different model systems.

Neuron-Astrocyte Liaison to Maintain Lipid Metabolism of Brain.

Neuron-astrocyte crosstalk is a tightly regulated process that is essential for overall proper functioning of the brain. Maria S. Ioannou et al. (Cell, 2019) revealed a novel and compelling function of neuron-astrocyte crosstalk that explains how neurons cope with their accumulating toxic lipid particles under various scenarios.

Neurodegenerative diseases: model organisms, pathology and autophagy.

A proteostasis view of neurodegeneration (ND) identifies protein aggregation as a leading causative reason for damage seen at the cellular and organ levels. While investigative therapies that aim at dissolving aggregates have failed, and the promises of silencing expression of ND associated pathogenic proteins or the deployment of engineered induced pluripotent stem cells (iPSCs) are still in the horizon, emerging literature suggests degrading aggregates through autophagy-related mechanisms hold the current potential for a possible cure. Macroautophagy (hereafter autophagy) is an intracellular degradative pathway where superfluous or unwanted cellular cargoes (such as peroxisomes, mitochondria, ribosomes, intracellular bacteria and misfolded protein aggregates) are wrapped in double membrane vesicles called autophagosomes that eventually fuses with lysosomes for their degradation. The selective branch of autophagy that deals with identification, capture and degradation of protein aggregates is called aggrephagy. Here, we cover the workings of aggrephagy detailing its selectivity towards aggregates. The diverse cellular adaptors that bridge the aggregates with the core autophagy machinery in terms of autophagosome formation are discussed. In ND, essential protein quality control mechanisms fail as the constituent components also find themselves trapped in the aggregates. Thus, although cellular aggrephagy has the potential to be upregulated, its dysfunction further aggravates the pathogenesis. This phenomenonwhen combined with the fact that neurons can neither dilute out the aggregates by cell division nor the dead neurons can be replaced due to low neurogenesis, makes a compelling case for aggrephagy pathway as a potential therapeutic option.

Modulation of Autophagy by a Small Molecule Inverse Agonist of ERRα Is Neuroprotective.

Mechanistic insights into aggrephagy, a selective basal autophagy process to clear misfolded protein aggregates, are lacking. Here, we report and describe the role of Estrogen Related Receptor α (ERRα, HUGO Gene Nomenclature ESRRA), new molecular player of aggrephagy, in keeping autophagy flux in check by inhibiting autophagosome formation. A screen for small molecule modulators for aggrephagy identified ERRα inverse agonist XCT 790, that cleared α-synuclein aggregates in an autophagy dependent, but mammalian target of rapamycin (MTOR) independent manner. XCT 790 modulates autophagosome formation in an ERRα dependent manner as validated by siRNA mediated knockdown and over expression approaches. We show that, in a basal state, ERRα is localized on to the autophagosomes and upon autophagy induction by XCT 790, this localization is lost and is accompanied with an increase in autophagosome biogenesis. In a preclinical mouse model of Parkinson's disease (PD), XCT 790 exerted neuroprotective effects in the dopaminergic neurons of nigra by inducing autophagy to clear toxic protein aggregates and, in addition, ameliorated motor co-ordination deficits. Using a chemical biology approach, we unrevealed the role of ERRα in regulating autophagy and can be therapeutic target for neurodegeneration.

A novel autophagy modulator 6-Bio ameliorates SNCA/α-synuclein toxicity.

Parkinson disease (PD) is a life-threatening neurodegenerative movement disorder with unmet therapeutic intervention. We have identified a small molecule autophagy modulator, 6-Bio that shows clearance of toxic SNCA/α-synuclein (a protein implicated in synucleopathies) aggregates in yeast and mammalian cell lines. 6-Bio induces autophagy and dramatically enhances autolysosome formation resulting in SNCA degradation. Importantly, neuroprotective function of 6-Bio as envisaged by immunohistology and behavior analyses in a preclinical model of PD where it induces autophagy in dopaminergic (DAergic) neurons of mice midbrain to clear toxic protein aggregates suggesting that it could be a potential therapeutic candidate for protein conformational disorders.

Rationally designed peptidomimetic modulators of aß toxicity in Alzheimer's disease.

Alzheimer's disease is one of the devastating illnesses mankind is facing in the 21st century. The main pathogenic event in Alzheimer's disease is believed to be the aggregation of the ß-amyloid (Aß) peptides into toxic aggregates. Molecules that interfere with this process may act as therapeutic agents for the treatment of the disease. Use of recognition unit based peptidomimetics as inhibitors are a promising approach, as they exhibit greater protease stability compared to natural peptides. Here, we present peptidomimetic inhibitors of Aß aggregation designed based on the KLVFF (P1) sequence that is known to bind Aß aggregates. We improved inhibition efficiency of P1 by introducing multiple hydrogen bond donor-acceptor moieties (thymine/barbiturate) at the N-terminal (P2 and P3), and blood serum stability by modifying the backbone by incorporating sarcosine (N-methylglycine) units at alternate positions (P4 and P5). The peptidomimetics showed moderate to good activity in both inhibition and dissolution of Aß aggregates as depicted by thioflavin assay, circular dichroism (CD) measurements and microscopy (TEM). The activity of P4 and P5 were studied in a yeast cell model showing Aß toxicity. P4 and P5 could rescue yeast cells from Aß toxicity and Aß aggregates were cleared by the process of autophagy.

Fiberoptic intubation through laryngeal mask airway for management of difficult airway in a child with Klippel-Feil syndrome.

The ideal airway management modality in pediatric patients with syndromes like Klippel-Feil syndrome is a great challenge and is technically difficult for an anesthesiologist. Half of the patients present with the classic triad of short neck, low hairline, and fusion of cervical vertebra. Numerous associated anomalies like scoliosis or kyphosis, cleft palate, respiratory problems, deafness, genitourinary abnormalities, Sprengel's deformity (wherein the scapulae ride high on the back), synkinesia, cervical ribs, and congenital heart diseases may further add to the difficulty. Fiberoptic bronchoscopy alone can be technically difficult and patient cooperation also becomes very important, which is difficult in pediatric patients. Fiberoptic bronchoscopy with the aid of supraglottic airway devices is a viable alternative in the management of difficult airway in children. We report a case of Klippel-Feil syndrome in an 18-month-old girl posted for cleft palate surgery. Imaging of spine revealed complete fusion of the cervical vertebrae with hypoplastic C3 and C6 vertebrae and thoracic kyphosis. We successfully managed airway in this patient by fiberoptic intubation through classic laryngeal mask airway (LMA). After intubation, we used second smaller endotracheal tube (ETT) to stabilize and elongate the first ETT while removing the LMA.

Synthesis of Hybrid Cyclic Peptoids and Identification of Autophagy Enhancer.

Cyclic peptoids are potential candidates for diverse biological activities. However, applications of cyclic peptoids are limited by the synthetic difficulties, conformational flexibility of large cyclic peptoids, and lack of secondary amide in the backbone. Herein, an elegant methodology for the synthesis of small and medium-size cyclic hybrid peptoids is developed. α N-Alkyl and α N-acyl substituents in N-(2-aminoethyl)glycine monomers enforce intra- and intermolecular cyclization to form stable six- and 12-membered cyclic products, respectively. NMR studies show inter- and intramolecular hydrogen bonding in six- and 12-membered cyclic peptoids, respectively. Screening of a cyclic peptoid library resulted in the identification of a potential candidate that enhanced autophagic degradation of cargo in a live cell model. Such upregulation of autophagy using small molecules is a promising approach for elimination of intracellular pathogens and neurodegenerative protein aggregates.

Severe renal injuries in children following blunt abdominal trauma: selective management and outcome.

INTRODUCTION: Blunt trauma accounts for the majority of pediatric renal injuries. Most injuries are often minor and can be managed without surgical intervention. We have retrospectively reviewed our series of children with severe (grade IV/V) renal injuries, their management and outcome. MATERIALS AND METHODS: Medical records of children less than 18 years with renal injuries were reviewed. The cause of injury, time following injury, management and outcome in these children were recorded. The outcome data were analyzed. RESULTS: During the period between January 1996 and December 2008, 43 children with grade IV/V renal injuries were admitted with blunt abdominal trauma. Ten of these 43 children underwent exploration and 33 initially managed non-operatively. Two of these 33 children on non-operative management needed nephrectomy for vascular injury and delayed haemorrhage. CONCLUSIONS: Most children with grade IV/V renal injury following blunt trauma can be managed non-operatively. Management can be properly planned and executed based on clinical features, CT imaging and staging of renal injuries. Surgical intervention is needed for associated abdominal organ injuries and renal vascular injuries.