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The Journal of Clinical Investigation Jun 2023Neurons are markedly compartmentalized, which makes them reliant on axonal transport to maintain their health. Axonal transport is important for anterograde delivery of... (Review)
Review
Neurons are markedly compartmentalized, which makes them reliant on axonal transport to maintain their health. Axonal transport is important for anterograde delivery of newly synthesized macromolecules and organelles from the cell body to the synapse and for the retrograde delivery of signaling endosomes and autophagosomes for degradation. Dysregulation of axonal transport occurs early in neurodegenerative diseases and plays a key role in axonal degeneration. Here, we provide an overview of mechanisms for regulation of axonal transport; discuss how these mechanisms are disrupted in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, hereditary spastic paraplegia, amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease; and discuss therapeutic approaches targeting axonal transport.
Topics: Humans; Axonal Transport; Neurodegenerative Diseases; Neurons; Alzheimer Disease; Parkinson Disease
PubMed: 37259916
DOI: 10.1172/JCI168554 -
Advances in Experimental Medicine and... 2023For the survival and maintenance of retinal ganglion cells (RGCs), axonal transportation is fundamental. Axonal transportation defects can cause severe neuropathies... (Review)
Review
For the survival and maintenance of retinal ganglion cells (RGCs), axonal transportation is fundamental. Axonal transportation defects can cause severe neuropathies leading to neuronal loss. Axonal transport defects usually precede axonal degeneration and RGC loss in disease models. To date, the main causes of axonal transport defects have not been fully understood. Therefore, elucidation of the mechanisms that lead to transport defects will help us to develop novel therapeutic targets and early diagnostic tools. In this review, we provide an overview of optic neuropathies and axonal degeneration with a focus on axonal transport.
Topics: Animals; Humans; Retinal Ganglion Cells; Axonal Transport; Disease Models, Animal; Axons; Optic Nerve Diseases
PubMed: 37440037
DOI: 10.1007/978-3-031-27681-1_32 -
Seminars in Cell & Developmental Biology Mar 2020Because of the extremely polarized morphology, the proper functioning of neurons largely relies on the efficient cargo transport along the axon. Axonal transport defects... (Review)
Review
Because of the extremely polarized morphology, the proper functioning of neurons largely relies on the efficient cargo transport along the axon. Axonal transport defects have been reported in multiple neurodegenerative diseases as an early pathological feature. The discovery of mutations in human genes involved in the transport machinery provide a direct causative relationship between axonal transport defects and neurodegeneration. Here, we summarize the current genetic findings related to axonal transport in neurodegenerative diseases, and we discuss the relationship between axonal transport defects and other pathological changes observed in neurodegeneration. In addition, we summarize the therapeutic approaches targeting the axonal transport machinery in studies of neurodegenerative diseases. Finally, we review the technical advances in tracking axonal transport both in vivo and in vitro.
Topics: Animals; Axonal Transport; Humans; Mutation; Neurodegenerative Diseases
PubMed: 31542222
DOI: 10.1016/j.semcdb.2019.07.010 -
Acta Neuropathologica Jul 2017The transport of mitochondria and other cellular components along the axonal microtubule cytoskeleton plays an essential role in neuronal survival. Defects in this... (Review)
Review
The transport of mitochondria and other cellular components along the axonal microtubule cytoskeleton plays an essential role in neuronal survival. Defects in this system have been linked to a large number of neurological disorders. In multiple sclerosis (MS) and associated models such as experimental autoimmune encephalomyelitis (EAE), alterations in axonal transport have been shown to exist before neurodegeneration occurs. Genome-wide association (GWA) studies have linked several motor proteins to MS susceptibility, while neuropathological studies have shown accumulations of proteins and organelles suggestive for transport deficits. A reduced effectiveness of axonal transport can lead to neurodegeneration through inhibition of mitochondrial motility, disruption of axoglial interaction or prevention of remyelination. In MS, demyelination leads to dysregulation of axonal transport, aggravated by the effects of TNF-alpha, nitric oxide and glutamate on the cytoskeleton. The combined effect of all these pathways is a vicious cycle in which a defective axonal transport system leads to an increase in ATP consumption through loss of membrane organization and a reduction in available ATP through inhibition of mitochondrial transport, resulting in even further inhibition of transport. The persistent activity of this positive feedback loop contributes to neurodegeneration in MS.
Topics: Animals; Axonal Transport; Humans; Multiple Sclerosis
PubMed: 28315956
DOI: 10.1007/s00401-017-1697-7 -
Current Opinion in Neurobiology Aug 2018Lysosomes perform degradative functions that are important for all cells. However, neurons are particularly dependent on optimal lysosome function due to their extremes... (Review)
Review
Lysosomes perform degradative functions that are important for all cells. However, neurons are particularly dependent on optimal lysosome function due to their extremes of longevity, size and polarity. Axons in particular exemplify the major spatial challenges faced by neurons in the maintenance of lysosome biogenesis and function. What impact does this have on the regulation and functions of lysosomes in axons? This review focuses on the mechanisms whereby axonal lysosome biogenesis, transport and function are adapted to meet neuronal demand. Important features include the dynamic relationship between endosomes, autophagosomes and lysosomes as well as the transport mechanisms that support the movement of lysosome precursors in axons. A picture is emerging wherein intermediates in the lysosome maturation processes that would only exist transiently within the crowded confines of a neuronal cell body are spatially and temporally separated over the extreme distances encountered in axons. Axons may thus offer significant opportunities for the analysis of the mechanisms that control lysosome biogenesis. Insights from the genetics and pathology of human neurodegenerative diseases furthermore emphasize the importance of efficient axonal transport of lysosomes and their precursors.
Topics: Animals; Axonal Transport; Humans; Lysosomes; Neurons
PubMed: 29529416
DOI: 10.1016/j.conb.2018.02.020 -
Current Opinion in Cell Biology Feb 1989
Review
Topics: Animals; Axonal Transport; Axons; Biological Transport; Cell Compartmentation
PubMed: 2483519
DOI: 10.1016/s0955-0674(89)80043-2 -
Journal of Neuromuscular Diseases 2019Axonal transport is a highly complex process essential for sustaining proper neuronal functioning. Disturbances can result in an altered neuronal homeostasis,... (Review)
Review
Axonal transport is a highly complex process essential for sustaining proper neuronal functioning. Disturbances can result in an altered neuronal homeostasis, aggregation of cargoes, and ultimately a dying-back degeneration of neurons. The impact of dysfunction in axonal transport is shown by genetic defects in key proteins causing a broad spectrum of neurodegenerative diseases, including inherited peripheral neuropathies. In this review, we provide an overview of the cytoskeletal components, molecular motors and adaptor proteins involved in axonal transport mechanisms and their implication in neuronal functioning. In addition, we discuss the involvement of axonal transport dysfunction in neurodegenerative diseases with a particular focus on inherited peripheral neuropathies. Lastly, we address some recent scientific advances most notably in therapeutic strategies employed in the area of axonal transport, patient-derived iPSC models, in vivo animal models, antisense-oligonucleotide treatments, and novel chemical compounds.
Topics: Adaptor Proteins, Signal Transducing; Animals; Axonal Transport; Charcot-Marie-Tooth Disease; Humans; Mitochondrial Proteins; Mutation; Peripheral Nervous System Diseases
PubMed: 31561383
DOI: 10.3233/JND-190427 -
Molecular and Cellular Neurosciences Dec 2022Axonal transport is a major cellular process that mediates bidirectional signaling between the soma and synapse, enabling both intracellular and intercellular...
Axonal transport is a major cellular process that mediates bidirectional signaling between the soma and synapse, enabling both intracellular and intercellular communications. Cellular materials, such as proteins, RNAs, and organelles, are transported by molecular motor proteins along cytoskeletal highways in a highly regulated manner. Several studies have demonstrated that axonal transport is central to normal neuronal function, plasticity, and memory storage. Importantly, disruptions in axonal transport result in neuronal dysfunction and are associated with several neurodegenerative disorders. However, we do not know much about axonal transport deficits in neuropsychiatric disorders. Here, we briefly discuss our current understanding of the role of axonal transport in schizophrenia, bipolar and autism.
Topics: Axonal Transport; Synapses; Neurons; Signal Transduction; Axons
PubMed: 36252719
DOI: 10.1016/j.mcn.2022.103786 -
Neurobiology of Disease Jan 2018Intra-neuronal protein aggregates made of fibrillar alpha-synuclein (α-syn) are the hallmark of Parkinson's disease (PD). With time, these aggregates spread through the... (Review)
Review
Intra-neuronal protein aggregates made of fibrillar alpha-synuclein (α-syn) are the hallmark of Parkinson's disease (PD). With time, these aggregates spread through the brain following axonal projections. Understanding the mechanism of this spread is central to the study of the progressive nature of PD. Here we review data relevant to the uptake, transport and release of α-syn fibrils. We summarize several cell surface receptors that regulate the uptake of α-syn fibrils by neurons. The aggregates are then transported along axons, both in the anterograde and retrograde direction. The kinetics of transport suggests that they are part of the slow component b of axonal transport. Recent findings indicate that aggregated α-syn is secreted by neurons by non-canonical pathways that may implicate various molecular chaperones including USP19 and the DnaJ/Hsc70 complex. Additionally, α-syn fibrils may also be released and transmitted from neuron-to-neuron via exosomes and tunneling nanotubes. Understanding these different mechanisms and molecular players underlying α-syn spread is crucial for the development of therapies that could halt the progression of α-syn-related degenerative diseases.
Topics: Animals; Axonal Transport; Humans; Neurodegenerative Diseases; Neurons; alpha-Synuclein
PubMed: 28323023
DOI: 10.1016/j.nbd.2017.03.007 -
Neuron Oct 2014Axonal transport is essential for neuronal function, and many neurodevelopmental and neurodegenerative diseases result from mutations in the axonal transport machinery.... (Review)
Review
Axonal transport is essential for neuronal function, and many neurodevelopmental and neurodegenerative diseases result from mutations in the axonal transport machinery. Anterograde transport supplies distal axons with newly synthesized proteins and lipids, including synaptic components required to maintain presynaptic activity. Retrograde transport is required to maintain homeostasis by removing aging proteins and organelles from the distal axon for degradation and recycling of components. Retrograde axonal transport also plays a major role in neurotrophic and injury response signaling. This review provides an overview of axonal transport pathways and discusses their role in neuronal function.
Topics: Animals; Axonal Transport; Axons; Humans; Neurodegenerative Diseases; Neurons; Organelles; Signal Transduction
PubMed: 25374356
DOI: 10.1016/j.neuron.2014.10.019