Defective axonal transport in motor neuron disease

El-Kadi, Ali Morsi; Soura, Violetta; Hafezparast, Majid

doi:10.1002/jnr.21188

Cited by 35 publications

(36 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Disturbances of neuronal transport have been suggested as potential causal factors in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Data from cell cultures and preclinical models suggest that abnormal microtubule (MT) dynamics and MT-based neuronal transport may play a role (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

“…Data from cell cultures and preclinical models suggest that abnormal microtubule (MT) dynamics and MT-based neuronal transport may play a role (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). The recent development of an in vivo stable isotope-mass spectrometric technique for measuring the turnover of MTs provides insights regarding neurodegeneration (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cerebrospinal fluid–based kinetic biomarkers of axonal transport in monitoring neurodegeneration

Fanara

Wong²,

Husted³

et al. 2012

J. Clin. Invest.

View full text Add to dashboard Cite

Progress in neurodegenerative disease research is hampered by the lack of biomarkers of neuronal dysfunction. We here identified a class of cerebrospinal fluid-based (CSF-based) kinetic biomarkers that reflect altered neuronal transport of protein cargo, a common feature of neurodegeneration. After a pulse administration of heavy water ( 2 H 2 O), distinct, newly synthesized 2 H-labeled neuronal proteins were transported to nerve terminals and secreted, and then appeared in CSF. In 3 mouse models of neurodegeneration, distinct 2 H-cargo proteins displayed delayed appearance and disappearance kinetics in the CSF, suggestive of aberrant transport kinetics. Microtubule-modulating pharmacotherapy normalized CSF-based kinetics of affected 2 H-cargo proteins and ameliorated neurodegenerative symptoms in mice. After 2 H 2 O labeling, similar neuronal transport deficits were observed in CSF of patients with Parkinson's disease (PD) compared with non-PD control subjects, which indicates that these biomarkers are translatable and relevant to human disease. Measurement of transport kinetics may provide a sensitive method to monitor progression of neurodegeneration and treatment effects.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cerebrospinal fluid–based kinetic biomarkers of axonal transport in monitoring neurodegeneration

Fanara

Wong²,

Husted³

et al. 2012

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…However, there may be special conditions, such as the need for axon repair or growth, where neurons require cell soma organelles in their axons, so the regulatory system for organelle transport must include components that inhibit, as well as promote, axonal transport. The association of mutations in the axonal transport machinery with neurodegenerative disorders in mice and humans underscores the importance of a properly functioning transport system for the long-term viability of neurons (Holzbaur 2004;El-Kadi et al 2007;De Vos et al 2008;Millecamps and Julien 2013;Maday et al 2014).The neuron's axonal transport system consists of a system of microtubule tracks and motor proteins that carry cargos along the tracks, as well as proteins that regulate the system. Microtubules have an intrinsic plus-and minus-end polarity, and axonal microtubules are oriented with their plus-ends pointing outward toward the synaptic region (Burton and Paige 1981;Heidemann et al 1981;Baas and Lin 2011).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

UNC-16 (JIP3) Acts Through Synapse-Assembly Proteins to Inhibit the Active Transport of Cell Soma Organelles to Caenorhabditis elegans Motor Neuron Axons

Edwards¹,

Morrison²,

Yorks³

et al. 2015

Genetics

View full text Add to dashboard Cite

The conserved protein UNC-16 (JIP3) inhibits the active transport of some cell soma organelles, such as lysosomes, early endosomes, and Golgi, to the synaptic region of axons. However, little is known about UNC-16's organelle transport regulatory function, which is distinct from its Kinesin-1 adaptor function. We used an unc-16 suppressor screen in Caenorhabditis elegans to discover that UNC-16 acts through CDK-5 (Cdk5) and two conserved synapse assembly proteins: SAD-1 (SAD-A Kinase), and SYD-2 (Liprin-a). Genetic analysis of all combinations of double and triple mutants in unc-16(+) and unc-16(2) backgrounds showed that the three proteins (CDK-5, SAD-1, and SYD-2) are all part of the same organelle transport regulatory system, which we named the CSS system based on its founder proteins. Further genetic analysis revealed roles for SYD-1 (another synapse assembly protein) and STRADa (a SAD-1-interacting protein) in the CSS system. In an unc-16(2) background, loss of the CSS system improved the sluggish locomotion of unc-16 mutants, inhibited axonal lysosome accumulation, and led to the dynein-dependent accumulation of lysosomes in dendrites. Time-lapse imaging of lysosomes in CSS system mutants in unc-16(+) and unc-16(2) backgrounds revealed active transport defects consistent with the steady-state distributions of lysosomes. UNC-16 also uses the CSS system to regulate the distribution of early endosomes in neurons and, to a lesser extent, Golgi. The data reveal a new and unprecedented role for synapse assembly proteins, acting as part of the newly defined CSS system, in mediating UNC-16's organelle transport regulatory function.KEYWORDS Caenorhabditis elegans; axonal transport; JIP3; Cdk5; Liprin; SAD-A; dynein N EURONS have a unique architecture consisting of a cell soma, one or more dendrites that receive information, and a single axon, which can be a single process or intricately branched. Part of the axon is specialized to form synapses, which integrate and transmit information to other neurons or muscle cells via synaptic vesicles and dense core vesicles. This unique architecture and cell biology places extraordinary demands on the membrane-trafficking and transport machinery. In addition to transporting synaptic vesicles and dense core vesicles long distances into axons, motor neurons must also restrict, or even prevent, the flow of some organelles, including Golgi, lysosomes, and endosomes, into the synaptic region of their axons, which, under normal conditions, are relatively devoid of these organelles compared to cell somas. However, there may be special conditions, such as the need for axon repair or growth, where neurons require cell soma organelles in their axons, so the regulatory system for organelle transport must include components that inhibit, as well as promote, axonal transport. The association of mutations in the axonal transport machinery with neurodegenerative disorders in mice and humans underscores the importance of a properly functioning transport system for the long-term viab...

show abstract

“…However, mutant DYNC1H1 weakens this "gain-of-interaction", thus life span improvement in Loa/SOD1 G93A mice may occur by rescuing the balance between anterograde and retrograde transport. Thus DYNC1H1 may ultimately ameliorate the loss of axonal homeostasis or rescue the imbalance of retrograde and anterograde axonal input [19,22].…”

Section: G93amentioning

confidence: 99%

Cytoplasmic dynein: a key player in neurodegenerative and neurodevelopmental diseases

Chen

Cooper

et al. 2014

Sci. China Life Sci.

View full text Add to dashboard Cite

Cytoplasmic dynein is the most important molecular motor driving the movement of a wide range of cargoes towards the minus ends of microtubules. As a molecular motor protein, dynein performs a variety of basic cellular functions including organelle transport and centrosome assembly. In the nervous system, dynein has been demonstrated to be responsible for axonal retrograde transport. Many studies have revealed direct or indirect evidence of dynein in neurodegenerative diseases such as amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Alzheimer's disease, Parkinson's disease and Huntington's disease. Among them, a number of mutant proteins involved in various neurodegenerative diseases interact with dynein. Axonal transport disruption is presented as a common feature occurring in neurodegenerative diseases. Dynein heavy chain mutant mice also show features of neurodegenerative diseases. Moreover, defects of dynein-dependent processes such as autophagy or clearance of aggregation-prone proteins are found in most of these diseases. Lines of evidence have also shown that dynein is associated with neurodevelopmental diseases. In this review, we focus on dynein involvement in different neurological diseases and discuss potential underlying mechanisms. dynein, retrograde transport, pathogenesis, neurodegenerative diseases, neurodevelopmental diseases Citation:Chen XJ, Xu H, Cooper HM, Liu YB. Cytoplasmic dynein: a key player in neurodegenerative and neurodevelopmental diseases.

show abstract

Defective axonal transport in motor neuron disease

Abstract: The original article to which this Erratum refers was published in

Cited by 35 publications

References 79 publications

Cerebrospinal fluid–based kinetic biomarkers of axonal transport in monitoring neurodegeneration

Cerebrospinal fluid–based kinetic biomarkers of axonal transport in monitoring neurodegeneration

UNC-16 (JIP3) Acts Through Synapse-Assembly Proteins to Inhibit the Active Transport of Cell Soma Organelles to Caenorhabditis elegans Motor Neuron Axons

Cytoplasmic dynein: a key player in neurodegenerative and neurodevelopmental diseases

Contact Info

Product

Resources

About