Secondary nucleation in amyloid formation

Chemical Communications, Journal Year: 2018, Volume and Issue: 54(63), P. 8667 - 8684

Published: Jan. 1, 2018

Nucleation of new peptide and protein aggregates on the surfaces amyloid fibrils same or has emerged in past two decades as a major pathway for both generation molecular species responsible cellular toxicity autocatalytic proliferation aggregates. A key question current research is mechanism driving forces governing such processes, known secondary nucleation. In this context, analogies with other self-assembling systems which monomer-dependent nucleation been studied more than century provide valuable source inspiration. Here, we present short overview background then review recent results regarding amyloid-forming peptides proteins, focusing particular β (Aβ) from Alzheimer's disease, some examples α-synuclein Parkinson's disease. Monomer-dependent Aβ was discovered using combination kinetic experiments, global analysis, seeding experiments selective isotope-enrichment, pinpoint monomer origin fibril-catalyzed reaction. Insights into are gained variations solution conditions, temperature sequence. Selective inhibition explored an effective means to limit oligomer production toxicity. We also aimed at finding interaction partners oligomers generated by ongoing aggregation process. At end feature article bring forward outstanding questions testable mechanistic hypotheses formation.

Language: Английский

---

Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis

Chemical Reviews, Journal Year: 2019, Volume and Issue: 119(9), P. 5537 - 5606

Published: Jan. 4, 2019

Advances over the past 25 years have revealed much about how structural properties of membranes and associated proteins are linked to thermodynamics kinetics membrane protein (MP) folding. At same time biochemical progress has outlined cellular proteostasis networks mediate MP folding manage misfolding in cell. When combined with results from genomic sequencing, these studies established paradigms for molecular etiologies a variety diseases. This emerging framework paved way development new class small molecule “pharmacological chaperones” that bind stabilize misfolded variants, some which now clinical use. In this review, we comprehensively outline current perspectives on integral MPs as well mechanisms quality control. Based perspectives, highlight opportunities innovations bridge our understanding energetics nuanced complexity biological systems. Given many linkages between human disease, also examine exciting leverage advances address challenges therapeutics precision medicine.

Language: Английский

---

Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment

Molecular Cell, Journal Year: 2018, Volume and Issue: 73(5), P. 1001 - 1014.e8

Published: Dec. 4, 2018

Language: Английский

---

Initiation and propagation of α-synuclein aggregation in the nervous system

Molecular Neurodegeneration, Journal Year: 2020, Volume and Issue: 15(1)

Published: March 6, 2020

The two main pathological hallmarks of Parkinson's disease are loss dopamine neurons in the substantia nigra pars compacta and proteinaceous amyloid fibrils composed mostly α-synuclein, called Lewy pathology. Levodopa to enhance dopaminergic transmission remains one most effective treatment for alleviating motor symptoms (Olanow, Mov Disord 34:812-815, 2019). In addition, deep brain stimulation (Bronstein et al., Arch Neurol 68:165, 2011) modulate basal ganglia circuit activity successfully alleviates some symptoms. MRI guided focused ultrasound subthalamic nucleus is a promising therapeutic strategy as well (Martinez-Fernandez Lancet 17:54-63, 2018). However, date, there exists no that stops progression this disease. findings α-synuclein can be released from inherited through interconnected neural networks opened door discovering novel strategies prevent formation spread pathology with goal halting PD its tracks. This hypothesis based on discoveries pathologic aggregates induce endogenous protein adopt similar conformation, thus self-propagating. Phase I clinical trials currently ongoing test treatments such immunotherapy neuron extracellular aggregates. Although tremendous progress has been made understanding how forms spreads throughout brain, cell intrinsic factors also play critical role mechanisms increase levels, selective expression profiles distinct subtypes, mutations altered function proteins involved synthesis degradation, oxidative stress. Strategies should consider release propagation, mechanisms.

Language: Английский

---

Dysregulated Lipid Metabolism and Its Role in α-Synucleinopathy in Parkinson’s Disease

Frontiers in Neuroscience, Journal Year: 2019, Volume and Issue: 13

Published: April 11, 2019

Parkinson's disease (PD) is the second most common neurodegenerative disease, main pathological hallmark of which accumulation α-synuclein (α-syn) and formation filamentous aggregates called Lewy bodies in brainstem, limbic system, cortical areas. Lipidomics a newly emerging field can provide fresh insights new answers that will enhance our capacity for early diagnosis, tracking progression, predicting critical endpoints, identifying risk pre-symptomatic persons. In recent years, lipids have been implicated many aspects PD pathology. Biophysical lipidomic studies demonstrated α-syn binds preferentially not only to specific lipid families but also molecular species these lipid-protein complexes its interaction with synaptic membranes, influence oligomerization aggregation, interfere catalytic activity cytoplasmic enzymes lysosomal lipases, thereby affecting metabolism. The genetic link between aberrant metabolism even more direct, mutations

Language: Английский

---

A Comprehensive Review: Sphingolipid Metabolism and Implications of Disruption in Sphingolipid Homeostasis

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(11), P. 5793 - 5793

Published: May 28, 2021

Sphingolipids are a specialized group of lipids essential to the composition plasma membrane many cell types; however, they primarily localized within nervous system. The amphipathic properties sphingolipids enable their participation in variety intricate metabolic pathways. Sphingoid bases building blocks for all sphingolipid derivatives, comprising complex class lipids. biosynthesis and catabolism these play an integral role small- large-scale body functions, including domains signalling; proliferation, death, migration, invasiveness; inflammation; central system development. Recently, have become focus several fields research medical biological sciences, as bioactive been identified potent signalling messenger molecules. now being exploited therapeutic targets pathologies. Here we present comprehensive review structure metabolism functional roles cell. In addition, highlight pathologies, inflammatory disease, cystic fibrosis, cancer, Alzheimer’s Parkinson’s lysosomal storage disorders.

Language: Английский

---

Parkinson’s disease: proteinopathy or lipidopathy?

npj Parkinson s Disease, Journal Year: 2020, Volume and Issue: 6(1)

Published: Jan. 3, 2020

Abstract Lipids play a more significant role in Parkinson’s disease and its related brain disorders than is currently recognized, supporting “lipid cascade”. The 14 kDa protein α-synuclein (αS) strongly associated with (PD), dementia Lewy bodies (DLB), other synucleinopathies such as multiple system atrophy, even certain forms of Alzheimer’s disease. Rigorously deciphering the biochemistry αS native systems key to developing treatments. highly expressed brain, second most lipid-rich organ, has been proposed be lipid-binding that physiologically interacts phospholipids fatty acids (FAs). αS-rich cytoplasmic inclusions called neurites are hallmark lesions synucleinopathies. Excess αS–membrane interactions may trigger proteinaceous aggregation by stimulating primary nucleation. However, also exert toxicity prior or independent self-aggregation, e.g., via excessive membrane interactions, which promoted lipids FAs. A complex αS-lipid landscape exists, comprises both physiological pathological states αS. As novel insights about composition occur, new lipid-related PD drug candidates emerge, genome-wide association studies (GWAS) increasingly validate hits lipid-associated pathways, it seems timely review our current knowledge consider roles for these pathways

Language: Английский

---

Probiotic Bacillus subtilis Protects against α-Synuclein Aggregation in C. elegans

Cell Reports, Journal Year: 2020, Volume and Issue: 30(2), P. 367 - 380.e7

Published: Jan. 1, 2020

Recent discoveries have implicated the gut microbiome in progression and severity of Parkinson's disease; however, how bacteria affect such neurodegenerative disorders remains unclear. Here, we report that Bacillus subtilis probiotic strain PXN21 inhibits α-synuclein aggregation clears preformed aggregates an established Caenorhabditis elegans model synucleinopathy. This protection is seen young aging animals partly mediated by DAF-16. Multiple B. strains trigger protective effect via both spores vegetative cells, due to a biofilm formation worms release bacterial metabolites. We identify several host metabolic pathways differentially regulated response exposure, including sphingolipid metabolism. further demonstrate functional roles metabolism genes lagr-1, asm-3, sptl-3 anti-aggregation effect. Our findings provide basis for exploring disease-modifying potential as dietary supplement.

Language: Английский

---

Gut Microbial Ecosystem in Parkinson Disease: New Clinicobiological Insights from Multi‐Omics

Annals of Neurology, Journal Year: 2020, Volume and Issue: 89(3), P. 546 - 559

Published: Dec. 4, 2020

Gut microbiome alterations in Parkinson disease (PD) have been reported repeatedly, but their functional relevance remains unclear. Fecal metabolomics, which provide a readout of microbial activity, scarcely investigated. We investigated fecal and metabolome PD, clinical relevance.Two hundred subjects (104 patients, 96 controls) underwent extensive phenotyping. Stool samples were analyzed using 16S rRNA gene sequencing. metabolomics performed two platforms, nuclear magnetic resonance (NMR) spectroscopy liquid chromatography-mass spectrometry.Fecal composition PD was significantly different from controls, with the largest effect size seen NMR-based metabolome. Microbiome compositional differences remained significant after comprehensive confounder analyses. Differentially abundant metabolite features predicted changes versus controls included bioactive molecules putative neuroprotective effects (eg, short chain fatty acids [SCFAs], ubiquinones, salicylate) other compounds increasingly implicated neurodegeneration ceramides, sphingosine, trimethylamine N-oxide). In group, cognitive impairment, low body mass index (BMI), frailty, constipation, physical activity associated differences. Notably, SCFAs poorer cognition BMI. Lower butyrate levels correlated worse postural instability-gait disorder scores.Gut function is altered characterized by differentially metabolic that important biological insights into gut-brain pathophysiology. Their further supports role for metabolites as potential targets development new biomarkers therapies PD. ANN NEUROL 2021;89:546-559.

Language: Английский

---

Common Mechanisms Underlying α-Synuclein-Induced Mitochondrial Dysfunction in Parkinson’s Disease

Journal of Molecular Biology, Journal Year: 2023, Volume and Issue: 435(12), P. 167992 - 167992

Published: Feb. 2, 2023

Language: Английский

---