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Additional feedforward mechanism of Parkin activation via binding of phospho-UBL and RING0 in <em>trans</em>
Loss-of-function Parkin mutations lead to early-onset of Parkinson's disease. Parkin is an auto-inhibited ubiquitin E3 ligase activated by dual phosphorylation of its ubiquitin-like (Ubl) domain and ubiquitin by the PINK1 kinase. Herein, we demonstrate a competitive binding of the phospho-Ubl and RING2 domains towards the RING0 domain, which regulates Parkin activity. We show that phosphorylated Parkin can complex with native Parkin, leading to the activation of autoinhibited native Parkin in...
Glymphotherapeutics for Alzheimer's disease: Time to move the needle
Alzheimer's disease (AD), the most predominant neurodegenerative disease and a quintessential entity within the dementia umbrella, is a global public health crisis. While the lack of disease modifying therapies has been a weak point in AD treatment, the success of recently approved monoclonal antibody-based therapeutics (aducanumab and lecanemab) targeted at the removal of amyloid-beta (Aβ) peptides in the brain is still under debate. There are multiple safety concerns about these approved...
Recent advancement in understanding of Alzheimer's disease: Risk factors, subtypes, and drug targets and potential therapeutics
Alzheimer's disease (AD) is a significant neocortical degenerative disorder characterized by the progressive loss of neurons and secondary alterations in white matter tracts. Understanding the risk factors and mechanisms underlying AD is crucial for developing effective treatments. The risk factors associated with AD encompass a wide range of variables, including gender differences, family history, and genetic predispositions. Additionally, environmental factors such as air pollution and...
Dopaminergic neurons lacking Caspase-3 avoid apoptosis but undergo necrosis after MPTP treatment inducing a Galectin-3-dependent selective microglial phagocytic response
Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc). Apoptosis is thought to play a critical role in the progression of PD, and thus understanding the effects of antiapoptotic strategies is crucial for developing potential therapies. In this study, we developed a unique genetic model to selectively delete Casp3, the gene encoding the apoptotic protein caspase-3, in dopaminergic neurons...
Acetyl-DL-leucine in two individuals with REM sleep behavior disorder improves symptoms, reverses loss of striatal dopamine-transporter binding and stabilizes pathological metabolic brain pattern-case reports
Isolated REM Sleep Behavior Disorder (iRBD) is considered a prodrome of Parkinson's disease (PD). We investigate whether the potentially disease-modifying compound acetyl-DL-leucine (ADLL; 5 g/d) has an effect on prodromal PD progression in 2 iRBD-patients. Outcome parameters are RBD-severity sum-score (RBD-SS-3), dopamine-transporter single-photon emission computerized tomography (DAT-SPECT) and metabolic "Parkinson-Disease-related-Pattern (PDRP)"-z-score in ^(18)F-fluorodeoxyglucose positron...
Potential implications of natural compounds on aging and metabolic regulation
Aging is generally accompanied by a progressive loss of metabolic homeostasis. Targeting metabolic processes is an attractive strategy for healthy-aging. Numerous natural compounds have demonstrated strong anti-aging effects. This review summarizes recent findings on metabolic pathways involved in aging and explores the anti-aging effects of natural compounds by modulating these pathways. The potential anti-aging effects of natural extracts rich in biologically active compounds are also...
Exploring the dynamic evolution of lattice oxygen on exsolved-Mn<sub>2</sub>O<sub>3</sub>@SmMn<sub>2</sub>O<sub>5</sub> interfaces for NO Oxidation
Lattice oxygen in metal oxides plays an important role in the reaction of diesel oxidation catalysts, but the atomic-level understanding of structural evolution during the catalytic process remains elusive. Here, we develop a Mn(2)O(3)/SmMn(2)O(5) catalyst using a non-stoichiometric exsolution method to explore the roles of lattice oxygen in NO oxidation. The enhanced covalency of Mn-O bond and increased electron density at Mn^(3+) sites, induced by the interface between exsolved Mn(2)O(3) and...
A Boolean model explains phenotypic plasticity changes underlying hepatic cancer stem cells emergence
In several carcinomas, including hepatocellular carcinoma, it has been demonstrated that cancer stem cells (CSCs) have enhanced invasiveness and therapy resistance compared to differentiated cancer cells. Mathematical-computational tools could be valuable for integrating experimental results and understanding the phenotypic plasticity mechanisms for CSCs emergence. Based on the literature review, we constructed a Boolean model that recovers eight stable states (attractors) corresponding to the...
Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome
Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells^(1-3). One possible consequence of mitochondria transfer is energetic support of neighbouring cells; for example, exogenous healthy mitochondria can rescue cell-intrinsic defects in mitochondrial metabolism in cultured ρ⁰ cells or Ndufs4^(-)^(/-) peritoneal macrophages^(4-7). Exposing haematopoietic stem cells to purified mitochondria before autologous haematopoietic stem cell...
Senolytics target cellular senescence - but can they slow aging?
No abstract
Ferroptosis in Parkinson's disease -- The iron-related degenerative disease
Parkinson's disease (PD) is a prevalent and advancing age-related neurodegenerative disorder, distinguished by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Iron regional deposit in SNpc is a significant pathological characteristic of PD. Brain iron homeostasis is precisely regulated by iron metabolism related proteins, whereas disorder of these proteins can damage neurons and glial cells in the brain. Additionally, growing studies have reported iron...
Emerging microglial biology highlights potential therapeutic targets for Alzheimer's disease
Alzheimer's disease is a chronic degenerative disease of the central nervous system, which primarily affects elderly people and accounts for 70-80 % of dementia cases. The current prevailing amyloid cascade hypothesis suggests that Alzheimer's disease begins with the deposition of amyloid β (Aβ) in the brain. Major therapeutic strategies target Aβ production, aggregation, and clearance, although many clinical trials have shown that these therapeutic strategies are not sufficient to completely...
Structural and functional remodeling of neural networks in β-amyloid driven hippocampal hyperactivity
Early detection of Alzheimer's disease (AD) is essential for improving the patients outcomes and advancing our understanding of disease, allowing for timely intervention and treatment. However, accurate biomarkers are still lacking. Recent evidence indicates that hippocampal hyperexcitability precedes the diagnosis of AD decades ago, can predict cognitive decline. Thus, could hippocampal hyperactivity be a robust biomarker for early-AD, and what drives hippocampal hyperactivity in early-AD?...
ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer's disease through BDNF/NGFR signaling
Genetic variants in ABCA7, an Alzheimer's disease (AD)-associated gene, elevate AD risk, yet its functional relevance to the etiology is unclear. We generated a CRISPR-Cas9-mediated abca7 knockout zebrafish to explore ABCA7's role in AD. Single-cell transcriptomics in heterozygous abca7^(+/-) knockout combined with Aβ42 toxicity revealed that ABCA7 is crucial for neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), and nerve growth factor receptor (NGFR) expressions, which are crucial...
scEpiAge: an age predictor highlighting single-cell ageing heterogeneity in mouse blood
Ageing is the accumulation of changes and decline of function of organisms over time. The concept and biomarkers of biological age have been established, notably DNA methylation-based clocks. The emergence of single-cell DNA methylation profiling methods opens the possibility of studying the biological age of individual cells. Here, we generate a large single-cell DNA methylation and transcriptome dataset from mouse peripheral blood samples, spanning a broad range of ages. The number of genes...
Modeling aging and retinal degeneration with mitochondrial DNA mutation burden
Somatic mitochondrial DNA (mtDNA) mutation accumulation has been observed in individuals with retinal degenerative disorders. To study the effects of aging and mtDNA mutation accumulation in the retina, a polymerase gamma (POLG) exonuclease-deficient model, the Polg^(D257A) mutator mice (D257A), was used. POLG is an enzyme responsible for regulating mtDNA replication and repair. Retinas of young and older mice with this mutation were analyzed in vivo and ex vivo to provide new insights into the...
Context-dependent impact of the dietary non-essential amino acid tyrosine on Drosophila physiology and longevity
Dietary protein intake modulates growth, reproduction, and longevity by stimulating amino acid (AA)-sensing pathways. Essential AAs are often considered as limiting nutrients during protein scarcity, and the role of dietary non-essential AAs (NEAAs) is less explored. Although tyrosine has been reported to be crucial for sensing protein restriction in Drosophila larvae, its effect on adult physiology and longevity remains unclear. Here, using a synthetic diet, we perform a systematic...
Aggregate-selective removal of pathological tau by clustering-activated degraders
Selective degradation of pathological protein aggregates while sparing monomeric forms is of major therapeutic interest. The E3 ligase tripartite motif-containing protein 21 (TRIM21) degrades antibody-bound proteins in an assembly state-specific manner due to the requirement of TRIM21 RING domain clustering for activation, yet effective targeting of intracellular assemblies remains challenging. Here, we fused the RING domain of TRIM21 to a target-specific nanobody to create intracellularly...
Nuclear proteasomes buffer cytoplasmic proteins during autophagy compromise
Autophagy is a conserved pathway where cytoplasmic contents are engulfed by autophagosomes, which then fuse with lysosomes enabling their degradation. Mutations in core autophagy genes cause neurological conditions, and autophagy defects are seen in neurodegenerative diseases such as Parkinson's disease and Huntington's disease. Thus, we have sought to understand the cellular pathway perturbations that autophagy-perturbed cells are vulnerable to by seeking negative genetic interactions such as...
Immunometabolic effects of lactate on humoral immunity in healthy individuals of different ages
Aging is characterized by chronic systemic inflammation and metabolic changes. We compare the metabolic status of B cells from young and elderly donors and found that aging is associated with higher oxygen consumption rates, and especially higher extracellular acidification rates, measures of oxidative phosphorylation and of anaerobic glycolysis, respectively. Importantly, this higher metabolic status, which reflects age-associated expansion of pro-inflammatory B cells, is found associated with...