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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 -
Science (New York, N.Y.) Oct 2023Neurons relay information via specialized presynaptic compartments for neurotransmission. Unlike conventional organelles, the specialized apparatus characterizing the...
Neurons relay information via specialized presynaptic compartments for neurotransmission. Unlike conventional organelles, the specialized apparatus characterizing the neuronal presynapse must form de novo. How the components for presynaptic neurotransmission are transported and assembled is poorly understood. Our results show that the rare late endosomal signaling lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P] directs the axonal cotransport of synaptic vesicle and active zone proteins in precursor vesicles in human neurons. Precursor vesicles are distinct from conventional secretory organelles, endosomes, and degradative lysosomes and are transported by coincident detection of PI(3,5)P and active ARL8 via kinesin KIF1A to the presynaptic compartment. Our findings identify a crucial mechanism that mediates the delivery of synaptic vesicle and active zone proteins to developing synapses.
Topics: Humans; Axonal Transport; Kinesins; Neurons; Synaptic Vesicles; Phosphatidylinositol Phosphates
PubMed: 37824668
DOI: 10.1126/science.adg1075 -
Neurotherapeutics : the Journal of the... Oct 2021Inherited peripheral neuropathies are a genetically and phenotypically diverse group of disorders that lead to degeneration of peripheral neurons with resulting sensory... (Review)
Review
Inherited peripheral neuropathies are a genetically and phenotypically diverse group of disorders that lead to degeneration of peripheral neurons with resulting sensory and motor dysfunction. Genetic neuropathies that primarily cause axonal degeneration, as opposed to demyelination, are most often classified as Charcot-Marie-Tooth disease type 2 (CMT2) and are the focus of this review. Gene identification efforts over the past three decades have dramatically expanded the genetic landscape of CMT and revealed several common pathological mechanisms among various forms of the disease. In some cases, identification of the precise genetic defect and/or the downstream pathological consequences of disease mutations have yielded promising therapeutic opportunities. In this review, we discuss evidence for pathogenic overlap among multiple forms of inherited neuropathy, highlighting genetic defects in axonal transport, mitochondrial dynamics, organelle-organelle contacts, and local axonal protein translation as recurrent pathological processes in inherited axonal neuropathies. We also discuss how these insights have informed emerging treatment strategies, including specific approaches for single forms of neuropathy, as well as more general approaches that have the potential to treat multiple types of neuropathy. Such therapeutic opportunities, made possible by improved understanding of molecular and cellular pathogenesis and advances in gene therapy technologies, herald a new and exciting phase in inherited peripheral neuropathy.
Topics: Axonal Transport; Axons; Charcot-Marie-Tooth Disease; Humans; Mutation
PubMed: 34606075
DOI: 10.1007/s13311-021-01099-2 -
Cell Reports Apr 2022Understanding the pathogenic mechanisms of disease mutations is critical to advancing treatments. ALS-associated mutations in the gene encoding the microtubule motor...
Understanding the pathogenic mechanisms of disease mutations is critical to advancing treatments. ALS-associated mutations in the gene encoding the microtubule motor KIF5A result in skipping of exon 27 (KIF5A) and the encoding of a protein with a novel 39 amino acid residue C-terminal sequence. Here, we report that expression of ALS-linked mutant KIF5A results in dysregulated motor activity, cellular mislocalization, altered axonal transport, and decreased neuronal survival. Single-molecule analysis revealed that the altered C terminus of mutant KIF5A results in a constitutively active state. Furthermore, mutant KIF5A possesses altered protein and RNA interactions and its expression results in altered gene expression/splicing. Taken together, our data support the hypothesis that causative ALS mutations result in a toxic gain of function in the intracellular motor KIF5A that disrupts intracellular trafficking and neuronal homeostasis.
Topics: Amyotrophic Lateral Sclerosis; Axonal Transport; Gain of Function Mutation; Humans; Kinesins; Mutation
PubMed: 35385738
DOI: 10.1016/j.celrep.2022.110598 -
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 -
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 -
International Journal of Molecular... Apr 2022Glaucoma is a neurodegenerative disease that affects the retinal ganglion cells (RGCs) and leads to progressive vision loss. The first pathological signs can be seen at... (Review)
Review
Glaucoma is a neurodegenerative disease that affects the retinal ganglion cells (RGCs) and leads to progressive vision loss. The first pathological signs can be seen at the optic nerve head (ONH), the structure where RGC axons leave the retina to compose the optic nerve. Besides damage of the axonal cytoskeleton, axonal transport deficits at the ONH have been described as an important feature of glaucoma. Axonal transport is essential for proper neuronal function, including transport of organelles, synaptic components, vesicles, and neurotrophic factors. Impairment of axonal transport has been related to several neurodegenerative conditions. Studies on axonal transport in glaucoma include analysis in different animal models and in humans, and indicate that its failure happens mainly in the ONH and early in disease progression, preceding axonal and somal degeneration. Thus, a better understanding of the role of axonal transport in glaucoma is not only pivotal to decipher disease mechanisms but could also enable early therapies that might prevent irreversible neuronal damage at an early time point. In this review we present the current evidence of axonal transport impairment in glaucomatous neurodegeneration and summarize the methods employed to evaluate transport in this disease.
Topics: Animals; Axonal Transport; Axons; Disease Models, Animal; Glaucoma; Neurodegenerative Diseases; Retinal Ganglion Cells
PubMed: 35409291
DOI: 10.3390/ijms23073935 -
Current Opinion in Neurobiology Aug 2020Slow axonal transport conveys cytosolic and cytoskeletal proteins into axons and synapses at overall velocities that are several orders of magnitude slower than the fast... (Review)
Review
Slow axonal transport conveys cytosolic and cytoskeletal proteins into axons and synapses at overall velocities that are several orders of magnitude slower than the fast transport of membranous organelles such as vesicles and mitochondria. The phenomenon of slow transport was characterized by in vivo pulse-chase radiolabeling studies done decades ago, and proposed models emphasized an orderly cargo-movement, with apparent cohesive transport of multiple proteins and subcellular structures along axons over weeks to months. However, visualization of cytosolic and cytoskeletal cargoes in cultured neurons at much higher temporal and spatial resolution has revealed an unexpected diversity in movement - ranging from a diffusion-like biased motion, to intermittent cargo dynamics and unusual polymerization-based transport paradigms. This review provides an updated view of slow axonal transport and explores emergent mechanistic themes in this enigmatic rate-class.
Topics: Axonal Transport; Axons; Cytoskeletal Proteins; Cytoskeleton; Neurons
PubMed: 32361600
DOI: 10.1016/j.conb.2020.03.015 -
Life Science Alliance Oct 2022Turnover of synaptic vesicle (SV) proteins is vital for the maintenance of healthy and functional synapses. SV protein turnover is driven by neuronal activity in an...
Turnover of synaptic vesicle (SV) proteins is vital for the maintenance of healthy and functional synapses. SV protein turnover is driven by neuronal activity in an endosomal sorting complex required for transport (ESCRT)-dependent manner. Here, we characterize a critical step in this process: axonal transport of ESCRT-0 component Hrs, necessary for sorting proteins into the ESCRT pathway and recruiting downstream ESCRT machinery to catalyze multivesicular body (MVB) formation. We find that neuronal activity stimulates the formation of presynaptic endosomes and MVBs, as well as the motility of Hrs+ vesicles in axons and their delivery to SV pools. Hrs+ vesicles co-transport ESCRT-0 component STAM1 and comprise a subset of Rab5+ vesicles, likely representing pro-degradative early endosomes. Furthermore, we identify kinesin motor protein KIF13A as essential for the activity-dependent transport of Hrs to SV pools and the degradation of SV membrane proteins. Together, these data demonstrate a novel activity- and KIF13A-dependent mechanism for mobilizing axonal transport of ESCRT machinery to facilitate the degradation of SV membrane proteins.
Topics: Axonal Transport; Endosomal Sorting Complexes Required for Transport; Endosomes; Proteolysis; Synaptic Vesicles
PubMed: 35636965
DOI: 10.26508/lsa.202000745 -
Cell Reports Sep 2022Deficits in mitochondrial transport are a common feature of neurodegenerative diseases. We investigated whether loss of components of the mitochondrial transport...
Deficits in mitochondrial transport are a common feature of neurodegenerative diseases. We investigated whether loss of components of the mitochondrial transport machinery impinge directly on metabolic stress, neuronal death, and circuit dysfunction. Using multiphoton microscope live imaging, we showed that ocular hypertension, a major risk factor in glaucoma, disrupts mitochondria anterograde axonal transport leading to energy decline in vulnerable neurons. Gene- and protein-expression analysis revealed loss of the adaptor disrupted in schizophrenia 1 (Disc1) in retinal neurons subjected to high intraocular pressure. Disc1 gene delivery was sufficient to rescue anterograde transport and replenish axonal mitochondria. A genetically encoded ATP sensor combined with longitudinal live imaging showed that Disc1 supplementation increased ATP production in stressed neurons. Disc1 gene therapy promotes neuronal survival, reverses abnormal single-cell calcium dynamics, and restores visual responses. Our study demonstrates that enhancing anterograde mitochondrial transport is an effective strategy to alleviate metabolic stress and neurodegeneration.
Topics: Adenosine Triphosphate; Axonal Transport; Dietary Supplements; Mitochondria; Nerve Tissue Proteins
PubMed: 36103832
DOI: 10.1016/j.celrep.2022.111324