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Cytoplasmic dynein heavy chain: the servant of many masters.

Schiavo G, Greensmith L, Hafezparast M, Fisher EM - Trends Neurosci. (2013)

Bottom Line: This complex comprises different subunits assembled on a cytoplasmic dynein heavy chain 1 (DYNC1H1) dimer.Cytoplasmic dynein is particularly important for neurons because it carries essential signals and organelles from distal sites to the cell body.Additionally, several DYNC1H1 mutations have recently been found in human patients that give rise to a broad spectrum of developmental and midlife-onset disorders.

View Article: PubMed Central - PubMed

Affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, National Hospital for Neurology and Neurosurgery, University College London, Queen Square, London WC1N 3BG, UK; Molecular NeuroPathobiology, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. Electronic address: giampietro.schiavo@ucl.ac.uk.

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Quantitative analysis of axonal retrograde transport by intravital microscopy. (A) Axonal retrograde transport of signalling endosomes containing a fluorescently labelled atoxic fragment of tetanus neurotoxin was monitored in single axons in the intact sciatic nerve by time-lapse confocal microscopy and shown as a time series [44]. (B) The deficit in axonal retrograde transport observed in early symptomatic SOD1G93A transgenic mice (74 ± 1.7 days; in red) is almost completely rescued by the Dync1h1Loa allele in Dync1h1+/LoaSOD1G93A double-mutant mice (in blue). The speed distribution profile displayed by Dync1h1+/LoaSOD1G93A mice overlaps with that observed in Dync1h1+/Loa animals (in green) and is slightly shifted towards lower speed values compared with wild type mice (in black) of similar age.
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fig0010: Quantitative analysis of axonal retrograde transport by intravital microscopy. (A) Axonal retrograde transport of signalling endosomes containing a fluorescently labelled atoxic fragment of tetanus neurotoxin was monitored in single axons in the intact sciatic nerve by time-lapse confocal microscopy and shown as a time series [44]. (B) The deficit in axonal retrograde transport observed in early symptomatic SOD1G93A transgenic mice (74 ± 1.7 days; in red) is almost completely rescued by the Dync1h1Loa allele in Dync1h1+/LoaSOD1G93A double-mutant mice (in blue). The speed distribution profile displayed by Dync1h1+/LoaSOD1G93A mice overlaps with that observed in Dync1h1+/Loa animals (in green) and is slightly shifted towards lower speed values compared with wild type mice (in black) of similar age.

Mentions: Based on the importance of cytoplasmic dynein in microtubule-dependent movement [42], the effects of Dync1h1 mutations on axonal transport were tested. Motor neuron cultures from Dync1h1Loa/Loa but not Dync1h1+/Loa embryos show a highly significant reduction in axonal retrograde transport [15,43]. The lack of an overt phenotype in heterozygous neurons is unexpected because mutant DYNC1H1 acts as a dimer [15,28]. The DYNC1H1Loa protein displays impaired run-lengths on microtubules [29] and the human DYNC1H1I584L protein has decreased binding to microtubules in the presence of ATP [26]. Both mutations have a similar biochemical profile, which is interesting given their proximity and highly conserved nature. The lack of an axonal transport phenotype in cultured Dync1h1+/Loa embryonic motor neurons was confirmed by assessing the retrograde transport of signalling endosomes in the sciatic nerve of adult Dync1h1+/Loa mice by intravital microscopy [44]. This technique allows the quantitative real-time assessment of the retrograde movement of transport organelles in the intact sciatic nerve of living mice and revealed only a minor drop in high transport speed in Dync1h1+/Loa mice (Figure 2), suggesting that only a subset of the specific functions of dynein is affected in these mice, causing a mild phenotype compatible with life.


Cytoplasmic dynein heavy chain: the servant of many masters.

Schiavo G, Greensmith L, Hafezparast M, Fisher EM - Trends Neurosci. (2013)

Quantitative analysis of axonal retrograde transport by intravital microscopy. (A) Axonal retrograde transport of signalling endosomes containing a fluorescently labelled atoxic fragment of tetanus neurotoxin was monitored in single axons in the intact sciatic nerve by time-lapse confocal microscopy and shown as a time series [44]. (B) The deficit in axonal retrograde transport observed in early symptomatic SOD1G93A transgenic mice (74 ± 1.7 days; in red) is almost completely rescued by the Dync1h1Loa allele in Dync1h1+/LoaSOD1G93A double-mutant mice (in blue). The speed distribution profile displayed by Dync1h1+/LoaSOD1G93A mice overlaps with that observed in Dync1h1+/Loa animals (in green) and is slightly shifted towards lower speed values compared with wild type mice (in black) of similar age.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3824068&req=5

fig0010: Quantitative analysis of axonal retrograde transport by intravital microscopy. (A) Axonal retrograde transport of signalling endosomes containing a fluorescently labelled atoxic fragment of tetanus neurotoxin was monitored in single axons in the intact sciatic nerve by time-lapse confocal microscopy and shown as a time series [44]. (B) The deficit in axonal retrograde transport observed in early symptomatic SOD1G93A transgenic mice (74 ± 1.7 days; in red) is almost completely rescued by the Dync1h1Loa allele in Dync1h1+/LoaSOD1G93A double-mutant mice (in blue). The speed distribution profile displayed by Dync1h1+/LoaSOD1G93A mice overlaps with that observed in Dync1h1+/Loa animals (in green) and is slightly shifted towards lower speed values compared with wild type mice (in black) of similar age.
Mentions: Based on the importance of cytoplasmic dynein in microtubule-dependent movement [42], the effects of Dync1h1 mutations on axonal transport were tested. Motor neuron cultures from Dync1h1Loa/Loa but not Dync1h1+/Loa embryos show a highly significant reduction in axonal retrograde transport [15,43]. The lack of an overt phenotype in heterozygous neurons is unexpected because mutant DYNC1H1 acts as a dimer [15,28]. The DYNC1H1Loa protein displays impaired run-lengths on microtubules [29] and the human DYNC1H1I584L protein has decreased binding to microtubules in the presence of ATP [26]. Both mutations have a similar biochemical profile, which is interesting given their proximity and highly conserved nature. The lack of an axonal transport phenotype in cultured Dync1h1+/Loa embryonic motor neurons was confirmed by assessing the retrograde transport of signalling endosomes in the sciatic nerve of adult Dync1h1+/Loa mice by intravital microscopy [44]. This technique allows the quantitative real-time assessment of the retrograde movement of transport organelles in the intact sciatic nerve of living mice and revealed only a minor drop in high transport speed in Dync1h1+/Loa mice (Figure 2), suggesting that only a subset of the specific functions of dynein is affected in these mice, causing a mild phenotype compatible with life.

Bottom Line: This complex comprises different subunits assembled on a cytoplasmic dynein heavy chain 1 (DYNC1H1) dimer.Cytoplasmic dynein is particularly important for neurons because it carries essential signals and organelles from distal sites to the cell body.Additionally, several DYNC1H1 mutations have recently been found in human patients that give rise to a broad spectrum of developmental and midlife-onset disorders.

View Article: PubMed Central - PubMed

Affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, National Hospital for Neurology and Neurosurgery, University College London, Queen Square, London WC1N 3BG, UK; Molecular NeuroPathobiology, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. Electronic address: giampietro.schiavo@ucl.ac.uk.

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Related in: MedlinePlus