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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Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration

Nature Neuroscience, Год журнала: 2019, Номер 22(2), С. 180 - 190

Опубликована: Янв. 8, 2019

Язык: Английский

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Axonal transport: Driving synaptic function

Science, Год журнала: 2019, Номер 366(6462)

Опубликована: Окт. 11, 2019

From trafficking to maintenance Neurons are remarkably polarized in that proteins made the cytosol often need travel many tens or hundreds of cell body lengths along axons their sites action synapse. Axonal transport these components is driven by molecular motors axonal microtubules. Guedes-Dias and Holzbaur review biology highlight roles this fundamental process plays organismal health. Science , issue p. eaaw9997

Язык: Английский

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Stability properties of neuronal microtubules

Cytoskeleton, Год журнала: 2016, Номер 73(9), С. 442 - 460

Опубликована: Фев. 18, 2016

Neurons are terminally differentiated cells that use their microtubule arrays not for cell division but rather as architectural elements required the elaboration of elongated axons and dendrites. In addition to acting compression-bearing struts provide shape neuron, microtubules also act directional railways organelle transport. The stability properties neuronal commonly discussed in biomedical literature crucial development maintenance nervous system, have recently gained attention central etiology neurodegenerative diseases. Drugs affect currently under investigation potential therapies disease injury system. There is often a lack consistency, however, how issue literature, this can design interpretation experiments well therapeutic regimens. Neuronal considered be more stable than dividing cells. On average, true, an abundant fraction neurons, there labile fraction. Both functionally important. Individual consist domains differ properties, these markedly composition they interact with various microtubule-related proteins neuron. Myriad pathways been contributors neurons. © 2016 Wiley Periodicals, Inc.

Язык: Английский

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Differentiation between Oppositely Oriented Microtubules Controls Polarized Neuronal Transport

Neuron, Год журнала: 2017, Номер 96(6), С. 1264 - 1271.e5

Опубликована: Ноя. 30, 2017

Microtubules are essential for polarized transport in neurons, but how their organization guides motor proteins to axons or dendrites is unclear. Because different motors recognize distinct microtubule properties, we used optical nanoscopy examine the relationship between orientations, stability, and modifications. Nanometric tracking of super-resolve microtubules determine polarity revealed that dendrites, stable acetylated mostly oriented minus-end out, while dynamic tyrosinated oppositely. In addition, with similar orientations modifications form bundles bias transport. Importantly, because plus-end-directed Kinesin-1 selectively interacts microtubules, this out into axons. contrast, Kinesin-3 prefers can enter both dendrites. This separation subsets oppositely constitutes a key architectural principle neuronal cytoskeleton enables sorting by proteins.

Язык: Английский

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Pathological mechanisms and therapeutic strategies for Alzheimer’s disease

Neural Regeneration Research, Год журнала: 2021, Номер 17(3), С. 543 - 543

Опубликована: Авг. 20, 2021

Alzheimer's disease is a rather complex neurodegenerative disease, which attributed to combination of multiple factors. Among the many pathological pathways, synaptic dysfunctions, such as synapses loss and deficits in plasticity, were thought be strongly associated with cognitive decline. The deficiencies various sorts neurotransmissions are responsible for multifarious symptoms example, cholinergic glutamatergic decline, excitatory inhibitory neurotransmission dyshomeostasis plasticity epileptiform symptoms, monoamine neuropsychiatric symptoms. Amyloid cascade hypothesis most popular theory explain pathogenesis attracts considerable attention. Multiple lines genetic evidence support predominant role amyloid beta pathology. Neurofibrillary tangles assembled by microtubule-associated protein tau other important histopathological characteristics brains. Cascade toxicity was proved lead neuron damage, neuroinflammation oxidative stress brain. Ageing main risk factor diseases, inflammation, stress, reduced metabolism, endocrine insufficiencies organ failures. These aging related factors also some contributing disease. In drug development, good therapeutic strategies have been investigated clinical evaluations. However, mechanism interplay among different call come out all-powerful therapies curing functions. This review seeks summarize representative treatments targeting pathways currently under Multi-target an emerging strategy treatment will highlighted.

Язык: Английский

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Microtubule-organizing centers: from the centrosome to non-centrosomal sites

Current Opinion in Cell Biology, Год журнала: 2016, Номер 44, С. 93 - 101

Опубликована: Сен. 23, 2016

Язык: Английский

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The Axon Initial Segment: An Updated Viewpoint

Journal of Neuroscience, Год журнала: 2018, Номер 38(9), С. 2135 - 2145

Опубликована: Янв. 29, 2018

At the base of axons sits a unique compartment called axon initial segment (AIS). The AIS generates and shapes action potential before it is propagated along axon. Neuronal excitability thus depends crucially on composition position, these adapt to developmental physiological conditions. also demarcates boundary between somatodendritic axonal compartments. Recent studies have brought insights into molecular architecture how regulates protein trafficking. This Viewpoints article summarizes current knowledge about highlights future challenges in understanding this key actor neuronal physiology.

Язык: Английский

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Microtubules gate tau condensation to spatially regulate microtubule functions

Nature Cell Biology, Год журнала: 2019, Номер 21(9), С. 1078 - 1085

Опубликована: Сен. 1, 2019

Язык: Английский

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The Role of the Microtubule Cytoskeleton in Neurodevelopmental Disorders

Frontiers in Cellular Neuroscience, Год журнала: 2018, Номер 12

Опубликована: Июнь 14, 2018

Neurons depend on the highly dynamic microtubule (MT) cytoskeleton for many different processes during early embryonic development including cell division and migration, intracellular trafficking signal transduction, as well proper axon guidance synapse formation. The coordination support from MTs is crucial newly formed neurons to migrate appropriately in order establish neural connections. Once connections are made, provide structural integrity maintain connectivity throughout development. Abnormalities migration due genetic mutations of MT-associated proteins can lead detrimental developmental defects. Growing evidence suggests that these associated with neurodevelopmental disorders, intellectual disabilities (ID) autism spectrum disorders (ASD). In this review article, we highlight role MT context neurodevelopment summarize various related may underlie or contribute disorders.

Язык: Английский

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