Hallmarks of neurodegenerative diseases

Cell, Год журнала: 2023, Номер 186(4), С. 693 - 714

Опубликована: Фев. 1, 2023

Summary

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks NDD: pathological protein aggregation, synaptic neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA RNA defects, inflammation, cell death. describe hallmarks, their biomarkers, interactions as a framework to study NDDs using holistic approach. The can serve basis defining pathogenic mechanisms, categorizing different based on primary stratifying patients within specific NDD, designing multi-targeted, personalized therapies effectively halt NDDs.

Язык: Английский

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Genetics and Pathogenesis of Parkinson's Syndrome

Annual Review of Pathology Mechanisms of Disease, Год журнала: 2022, Номер 18(1), С. 95 - 121

Опубликована: Сен. 13, 2022

Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops virtually unique form of syndrome. Clinical manifestations consist variable motor nonmotor features, myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly characterized by alpha-synuclein protein pathology throughout the central peripheral nervous systems, distribution varies pathologies modify PD or trigger similar manifestations. Nearly all influenced. More than 100 genes genetic loci have been identified, cases likely arise from interactions among many common rare variants. Despite its complex architecture, insights experimental dissection coalesce reveal unifying biological themes, including synaptic, lysosomal, mitochondrial, andimmune-mediated mechanisms pathogenesis. This emerging understanding syndrome, coupled advances in biomarkers targeted therapies, presages successful precision medicine strategies.

Язык: Английский

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Tunnelling nanotubes between neuronal and microglial cells allow bi-directional transfer of α-Synuclein and mitochondria

Cell Death and Disease, Год журнала: 2023, Номер 14(5)

Опубликована: Май 18, 2023

Abstract Tunnelling Nanotubes (TNTs) facilitate contact-mediated intercellular communication over long distances. Material transfer via TNTs can range from ions and intracellular organelles to protein aggregates pathogens. Prion-like toxic accumulating in several neurodegenerative pathologies, such as Alzheimer’s, Parkinson’s, Huntington’s diseases, have been shown spread not only between neurons, but also neurons-astrocytes, neurons-pericytes, indicating the importance of mediating neuron–glia interactions. TNT-like structures were reported microglia, however, their roles neuron-microglia interaction remain elusive. In this work, we quantitatively characterise microglial cytoskeletal composition, demonstrate that form human neuronal cells. We show α -Synuclein ( -Syn) increase global TNT-mediated connectivity cells, along with number TNT connections per cell pair. Homotypic formed heterotypic cells are furthermore be functional, allowing movement both -Syn mitochondria. Quantitative analysis shows transferred predominantly possibly a mechanism relieve burden accumulated aggregates. By contrast, microglia mitochondria preferably burdened healthy ones, likely potential rescue mechanism. Besides describing novel work allows us better understand cellular mechanisms spreading shedding light on role microglia.

Язык: Английский

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Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies

Cellular and Molecular Life Sciences, Год журнала: 2022, Номер 79(3)

Опубликована: Март 1, 2022

Abstract Protein misfolding is a general hallmark of protein deposition diseases, such as Alzheimer’s disease or Parkinson’s disease, in which different types aggregated species (oligomers, protofibrils and fibrils) are generated by the cells. Despite widespread interest, relationship between oligomers fibrils aggregation process spreading remains elusive. A large variety experimental evidences supported idea that soluble oligomeric proteins might be more toxic than larger fibrillar forms. Furthermore, lack correlation presence typical pathological inclusions sustained this debate. However, recent data show β-sheet core α-Synuclein (αSyn) unable to establish persistent interactions with lipid bilayers, but they can release responsible for an immediate dysfunction recipient neurons. Reversibly, could also contribute pathogenesis via neuron-to-neuron their direct cell-to-cell transfer generating new fibrils, following neuronal uptake. In Review, we discuss various mechanisms cellular caused αSyn, including oligomer toxicity, fibril toxicity spreading.

Язык: Английский

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Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes

Neuron, Год журнала: 2024, Номер 112(18), С. 3106 - 3125.e8

Опубликована: Июль 25, 2024

Microglia are crucial for maintaining brain health and neuron function. Here, we report that microglia establish connections with neurons using tunneling nanotubes (TNTs) in both physiological pathological conditions. These TNTs facilitate the rapid exchange of organelles, vesicles, proteins. In neurodegenerative diseases like Parkinson's Alzheimer's disease, toxic aggregates alpha-synuclein (α-syn) tau accumulate within neurons. Our research demonstrates use to extract from these aggregates, restoring neuronal health. Additionally, share their healthy mitochondria burdened neurons, reducing oxidative stress normalizing gene expression. Disrupting mitochondrial function antimycin A before TNT formation eliminates this neuroprotection. Moreover, co-culturing promoting rescues suppressed activity caused by α-syn or aggregates. Notably, TNT-mediated aggregate transfer is compromised carrying Lrrk22(Gly2019Ser) Trem2(T66M) (R47H) mutations, suggesting a role pathology variants diseases.

Язык: Английский

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Protective effect of the tunneling nanotube-TNFAIP2/M-sec system on podocyte autophagy in diabetic nephropathy

Autophagy, Год журнала: 2022, Номер 19(2), С. 505 - 524

Опубликована: Июнь 6, 2022

Podocyte injury leading to albuminuria is a characteristic feature of diabetic nephropathy (DN). Hyperglycemia and advanced glycation end products (AGEs) are major determinants DN. However, the underlying mechanisms podocyte remain poorly understood. The cytosolic protein TNFAIP2/M-Sec required for tunneling nanotubes (TNTs) formation, which membrane channels that transiently connect cells, allowing organelle transfer. Podocytes express TNFAIP2 form TNTs, but potential relevance TNFAIP2-TNT system in DN unknown. We studied expression both human experimental renal effect tnfaip2 deletion streptozotocin-induced Moreover, we explored role podocytes exposed diabetes-related insults. was overexpressed by exposre high glucose AGEs induced system. In mice, exacerbated albuminuria, function loss, injury, mesangial expansion. blockade autophagic flux due lysosomal dysfunction observed diabetes-injured vitro vivo deletion. TNTs allowed autophagosome lysosome exchange between podocytes, thereby ameliorating AGE-induced apoptosis. This protective abolished deletion, TNT inhibition, donor cell damage. By contrast, Tnfaip2 overexpression enhanced TNT-mediated transfer prevented autophagy conclusion, plays an important context may represent novel druggable target.Abbreviations: AGEs: products; AKT1: AKT serine/threonine kinase 1; AO: acridine orange; ALs: autolysosomes; APs: autophagosomes; BM: bone marrow; BSA: bovine serum albumin; CTSD: cathepsin D; DIC: differential interference contrast; DN: nephropathy; FSGS: focal segmental glomerulosclerosis; HG: glucose; KO: knockout; LAMP1: lysosomal-associated LMP: permeabilization; MAP1LC3/LC3: microtubule-associated 1 light chain 3; PI3K: phosphoinositide 3-kinase; STZ: streptozotocin; TNF: tumor necrosis factor; TNFAIP2: factor, alpha-induced 2; TNTs: nanotubes; WT: wild type.

Язык: Английский

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Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Авг. 22, 2022

Abstract Considerable evidence supports the release of pathogenic aggregates neuronal protein α-Synuclein (αSyn) into extracellular space. While this is proposed to instigate neuron-to-neuron transmission and spread αSyn pathology in synucleinopathies including Parkinson’s disease, molecular-cellular mechanism(s) remain unclear. To study this, we generated a new mouse model specifically immunoisolate lysosomes, established long-term culture where are produced within neurons without addition exogenous fibrils. We show that neuronally species accumulate lysosomes brains primary neurons. then find these via SNARE-dependent lysosomal exocytosis. The released non-membrane enveloped seeding-competent. Additionally, dependent on activity cytosolic Ca 2+ . These results propose exocytosis as central mechanism for aggregated degradation-resistant proteins from

Язык: Английский

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SARS-CoV-2: A Master of Immune Evasion

Biomedicines, Год журнала: 2022, Номер 10(6), С. 1339 - 1339

Опубликована: Июнь 7, 2022

Viruses and their hosts have coevolved for a long time. This coevolution places both the pathogen human immune system under selective pressure; on one hand, has evolved to combat viruses virally infected cells, while developed sophisticated mechanisms escape recognition destruction by system. SARS-CoV-2, that is causing current COVID-19 pandemic, shown remarkable ability antibody neutralization, putting vaccine efficacy at risk. One of virus’s evasion strategies mitochondrial sabotage: reactive oxygen species (ROS) production, physiology impaired, interferon antiviral response suppressed. Seminal studies identified an intra-cytoplasmatic pathway viral infection, which occurs through construction tunneling nanotubes (TNTs), hence enhancing infection avoiding surveillance. Another method evading monitoring disruption antigen presentation. In this scenario, SARS-CoV-2 reduces MHC-I molecule expression: SARS-CoV-2’s open reading frames (ORF 6 ORF 8) produce proteins specifically downregulate molecules. All these are also exploited other elude detection should be studied in depth improve effectiveness future treatments. Compared Wuhan strain or Delta variant, Omicron mutations impaired its generate syncytia, thus reducing pathogenicity. Conversely, allowed it neutralization preventing cellular recognition, making most contagious evasive variant date.

Язык: Английский

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Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models

Autophagy, Год журнала: 2022, Номер 18(5), С. 1127 - 1151

Опубликована: Март 15, 2022

Parkinson disease (PD) is a neurodegenerative disorder characterized by the abnormal intracellular accumulation of SNCA/α-synuclein. While exact mechanisms underlying SNCA pathology are not fully understood, increasing evidence suggests involvement autophagy as well lysosomal deficiencies. Because CTSD (cathepsin D) has been proposed to be major protease involved in degradation, its deficiency linked presence insoluble conformers brain mice and humans transcellular transmission aggregates. We here postulate that degradation can enhanced application recombinant human proform (rHsCTSD). Our results reveal rHsCTSD efficiently endocytosed neuronal cells, correctly targeted lysosomes matured an enzymatically active protease. In dopaminergic neurons derived from induced pluripotent stem cells (iPSC) PD patients harboring A53T mutation within gene, we confirm reduction after treatment with rHsCTSD. Moreover, demonstrate decrease pathological primary ctsd-deficient mouse model dosing Boosting activity only clearance murine tissue, but also restored endo-lysosome function. findings indicate critical for Thus, enzyme replacement strategies utilizing may therapeutic interest other synucleinopathies aiming burden.Abbreviations: aa: amino acid; SNCA/α-synuclein: synuclein alpha; APP: amyloid beta precursor protein; BBB: blood barrier; BF: basal forebrain; CBB: Coomassie Brilliant Blue; CLN: ceroid lipofuscinosis; CNL10: lipofuscinosis type 10; Corr.: corrected; CTSD: cathepsin D; CTSB: B; DA: dopaminergic; DA-iPSn: cell-derived neurons; dox: doxycycline; ERT: therapy; Fx: fornix, GBA/β-glucocerebrosidase: glucosylceramidase beta; h: hour; HC: hippocampus; HT: hypothalamus; i.c.: intracranially; IF: immunofluorescence; iPSC: cell; KO: knockout; LAMP1: associated membrane protein 1; LSDs: storage disorders; MAPT: microtubule tau; M6P: mannose-6-phosphate; M6PR: mannose-6-phosphate receptor; MB: midbrain; mCTSD: mature form CTSD; neurofil.: neurofilament; PD: disease; proCTSD: PRNP: prion RFU: relative fluorescence units; rHsCTSD: proCTSD; SAPC: Saposin C; SIM: structured illumination microscopy; T-insol: Triton-insoluble; T-sol: Triton-soluble; TEM: electron microscopy, TH: tyrosine hydroxylase; Thal: thalamus.

Язык: Английский

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Astrocytes: The Stars in Neurodegeneration?

Biomolecules, Год журнала: 2024, Номер 14(3), С. 289 - 289

Опубликована: Фев. 28, 2024

Today, neurodegenerative disorders like Alzheimer’s disease (AD), Parkinson’s (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) affect millions of people worldwide, as the average human lifespan increases, similarly grows number patients. For many decades, cognitive motoric decline has been explained by very apparent deterioration neurons in various regions brain spinal cord. However, more recent studies show that progression is greatly influenced vast population glial cells. Astrocytes are traditionally considered star-shaped cells on which rely heavily for their optimal homeostasis survival. Increasing amounts evidence depict how astrocytes lose supportive functions while simultaneously gaining toxic properties during neurodegeneration. Many these changes similar across diseases, this review, we highlight commonalities. We discuss astrocyte dysfunction drives neuronal demise a wide range but rather than categorizing based disease, aim to provide an overview currently known mechanisms. As such, review delivers different perspective causes neurodegeneration hope encourage further cross-disease into shared mechanisms, might ultimately disclose potentially common therapeutic entry points panel diseases.

Язык: Английский

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