Why neurons lose their spark?

[jd58]

Brilliant summary of "why neurons lose their spark' Graham well done.

[Graham]

The MND treatments in Phase 3 trials require mapping out. MNDA?? Then we know if as individuals we may be treated.

See item #15

[nunhead_man]

Indeed Graham thank you for letting us know.

Aside from Doug's question are you getting any support of the genetic counselling variety?

I'm wondering if your family are beginning to wonder, as mine are, what the implications are for their children if any.

[Doug Carpenter]

Thanks for letting us know Graham. Good luck with your research.

May I ask - how does your MND manifest itself?

Merry Christmas!

Doug

[Graham]

Merry Christmas Doug, Andy,

I have the DCTN1 gene mutation. It runs in my father's side and the majority have developed some form of condition as given in panelapp. I have drawn the MND straw. I am gathering my thoughts to dig into this further. It does fit with DCTN1.

Regards

[nunhead_man]

Hello Graham,

Thank you for these posts - as Doug says "mis-folded proteins and the cell's inability to remove them seem to be pretty universal in neurodegenerative diseases.

I just wish we could get the point where the particular mis-folding that causes MND could be identified and then we can get onto sorting out what the cause is

[Doug Carpenter]

Thanks for posting this Graham – very interesting. Mis-folded proteins and a cell’s inability to remove them seem to be pretty universal in neurodegenerative diseases.

Please could you also post the reference/citation to this paper.

[Billy106 – this is the reality of complex research into MND. Small steps….]

Doug

[Graham]

A motor neuron disease–associated mutation in p150Glued perturbs dynactin function and induces protein aggregation

Abstract
The microtubule motor cytoplasmic dynein and its activator dynactin drive vesicular transport and mitotic spindle organization. Dynactin is ubiquitously expressed in eukaryotes, but a G59S mutation in the p150Glued subunit of dynactin results in the specific degeneration of motor neurons. This mutation in the conserved cytoskeleton-associated protein, glycine-rich (CAP-Gly) domain lowers the affinity of p150Glued for microtubules and EB1. Cell lines from patients are morphologically normal but show delayed recovery after nocodazole treatment, consistent with a subtle disruption of dynein/dynactin function. The G59S mutation disrupts the folding of the CAP-Gly domain, resulting in aggregation of the p150Glued protein both in vitro and in vivo, which is accompanied by an increase in cell death in a motor neuron cell line. Overexpression of the chaperone Hsp70 inhibits aggregate formation and prevents cell death. These data support a model in which a point mutation in p150Glued causes both loss of dynein/dynactin function and gain of toxic function, which together lead to motor neuron cell death.
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Introduction
The microtubule motor cytoplasmic dynein and its activator dynactin, which mediate minus end–directed movement, have important roles in both interphase and dividing cells. In interphase cells, the dynein–dynactin complex is essential for vesicle and organelle transport, such as ER-to-Golgi vesicular trafficking (for review see Schroer, 2004). The dynein–dynactin motor complex also transports RNA particles (Carson et al., 2001), aggresomes (Johnston et al., 2002), and virus particles along microtubules (Dohner et al., 2002). During cell division, dynein and dynactin play a critical role in both nuclear envelope breakdown and spindle formation (for review see Schroer, 2004).
Consistent with these multiple cellular roles, dynein and dynactin function are required in higher eukaryotes. Loss of dynein or dynactin is lethal in Drosophila melanogaster (Gepner et al., 1996), and mice homozygous for loss of cytoplasmic dynein heavy chain die early in embryogenesis (Harada et al., 1998). Cells cultured from dynein heavy chain–null embryos show fragmented Golgi and a dispersal of endosomes and lysosomes throughout the cytoplasm (Harada et al., 1998).
Neurons appear to be particularly susceptible to defects in dynein–dynactin complex function. The dominant-negative mutation in D. melanogaster Glued, which encodes a truncated form of the p150Glued subunit of dynactin, shows defects that are most profound in neurons (Harte and Kankel, 1983). Two N-ethyl-N-nitrosurea–induced point mutations in cytoplasmic dynein heavy chain cause slowly progressive motor neuron disease in mice (Hafezparast et al., 2003). Legs at odd angles (Loa) and Cramping (Cra1) mice each carry missense mutations in a highly conserved domain of cytoplasmic dynein that mediates subunit interactions. When homozygous, these mutations are lethal; heterozygous mice exhibit progressive loss of motor neurons, leading to muscle weakness and atrophy (Hafezparast et al., 2003). A similar phenotype is observed in transgenic mice with a targeted disruption of dynactin in motor neurons (LaMonte et al., 2002).
In humans, a G59S missense mutation has been identified in the gene encoding p150Glued (DCTN1) in a kindred with slowly progressive motor neuron disease (Puls et al., 2003). Affected patients develop adult-onset vocal fold paralysis, facial weakness, and distal-limb muscle weakness and atrophy. Clinical, electrophysiological, and pathological investigations have confirmed the selective loss of motor neurons in this disorder (Puls et al., 2005). p150Glued is the dynactin subunit responsible for binding to dynein and microtubules (Vaughan and Vallee, 1995; Waterman-Storer et al., 1995). The G59S substitution occurs in the highly conserved NH2-terminal cytoskeleton-associated protein, glycine-rich (CAP-Gly) domain, which interacts directly with microtubules (Waterman-Storer et al., 1995) and the microtubule plus-end protein EB1 (Ligon et al., 2003).
In this study, we examined the biochemical and cellular effects of the G59S substitution in p150Glued. Our data suggest that the G59S mutation leads to both decreased microtubule binding and enhanced dynein and dynactin aggregation, suggesting that both loss of function and toxic gain of function contribute to the motor neuron degeneration observed in affected patients.
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Results
The G59S mutation disrupts the binding of p150Glued to microtubules and EB1
The G59S mutation is located within the highly conserved CAP-Gly domain of the p150Glued polypeptide, a domain that mediates the binding of dynactin to microtubules. We compared the microtubule binding affinities of wild-type and G59S p150Glued peptides (Fig. 1 A). The CAP-Gly domain of wild-type p150Glued, which spans residues 1–107, bound weakly to microtubules (unpublished data). This 1–107 peptide lacks the serine-rich region of p150Glued (111–191), which may be required for efficient microtubule binding by CAP-Gly proteins (Hoogenraad et al., 2000). In contrast, the binding of NH2-terminal residues 1–333 of the wild-type protein to microtubules was robust, with a K d of 1.1 ± 0.2 μM. The 1–333 fragment of p150Glued carrying the G59S mutation bound to microtubules with a K d of 2.6 ± 0.5 μM, indicating a modest decrease in affinity. More striking, however, was the observation that even at saturating microtubule concentrations, only half of the mutant protein was able to bind to microtubules in this assay (Fig. 1 B). Similar results were observed in experiments with full-length wild-type and G59S p150Glued (unpublished data).

Or in plain English...

This gene mutation doesn't make its subunits well and over time clog up axons and knacker 'em. Subunit Hsp70 [WD40] can oil it to make it work better.

[Graham]

Official Symbol - DCTN1provided by HGNC
Official Full Name - dynactin subunit 1provided by HGNC
Primary source - HGNC:HGNC:2711
See related - Ensembl:ENSG00000204843 MIM:601143
Gene type - protein coding
RefSeq status - REVIEWED
Organism - Homo sapiens
Lineage - Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo

Also known as - P135; DP-150; DAP-150


Summary

This gene encodes the largest subunit of dynactin, a macromolecular complex consisting of 10 subunits ranging in size from 22 to 150 kD. Dynactin binds to both microtubules and cytoplasmic dynein. Dynactin is involved in a diverse array of cellular functions, including ER-to-Golgi transport, the centripetal movement of lysosomes and endosomes, spindle formation, chromosome movement, nuclear positioning, and axonogenesis. This subunit interacts with dynein intermediate chain by its domains directly binding to dynein and binds to microtubules via a highly conserved glycine-rich cytoskeleton-associated protein (CAP-Gly) domain in its N-terminus. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. Mutations in this gene cause distal hereditary motor neuronopathy type VIIB (HMN7B) which is also known as distal spinal and bulbar muscular atrophy (dSBMA). [provided by RefSeq, Oct 2008]

Expression - Ubiquitous expression in brain (RPKM 71.1), testis (RPKM 43.6) and 25 other tissues See more

[Graham]

The DCTN1 gene provides instructions for making a protein called dynactin-1. At least two different versions of this protein are produced in cells. The two versions differ in size; the larger version is called p150-glued, and the smaller version is called p135.
Both versions of the dynactin-1 protein interact with several other proteins to form a group (a complex) of proteins called dynactin. The p150-glued version of dynactin-1 is the largest component (subunit) of the dynactin complex. This complex plays a critical role in cell division and the transport of materials within cells. To carry out these roles, the complex's p150-glued subunit attaches (binds) to a protein called dynein, which acts as a motor, and also binds to a track-like system of small tubes called microtubules. The dynactin complex, dynein, and microtubules work together like a conveyer belt to move materials within cells.
Researchers believe that the dynactin complex is particularly important for the proper function of axons, which are specialized extensions of nerve cells (neurons). Axons transmit impulses from nerve to nerve and from nerves to muscles. Axons can be quite long; some are more than 3 feet in length. The dynactin complex is a critical part of a rapid transport system that supplies axons with materials to keep them healthy and functioning efficiently.

[Graham]

Panelapp provides a clinical and scientific library of genes for rare diseases including various forms of MND.

https://www.genomicsengland.co.uk/about-genomics-england/panelapp/

So now, I must learn about my form of MND.

[Graham]

I now have my 'very likely' gene defect that has caused my MND. Now I am able to progress fixing it.

[Doug Carpenter]

Thanks Andy.

Yes, one more small step.

Doug

[Lynne K]

Thanks, very interesting. Lynne

[nunhead_man]

I saw this on Facebook today - I assume this is more progress in this area?

https://alsnewstoday.com/2019/02/28/strategy-potentially-prevent-tdp-43-aggregates-neurodegeneration/