Has a possible new lead been found in the fight against neurodegenerative diseases?

Good communication between brain cells is vital for optimal (mental) health. Mutations in the TBC1D24 gene inhibit this process, thereby causing neurodegeneration and epilepsy. Fruit flies with a defect in Skywalker, the fruit fly variant of TBC1D24, are being used as a model for neurodegeneration. Researchers from VIB and KU Leuven have succeeded in completely suppressing neurodegeneration in such fruit flies, by partially inhibiting the breakdown of 'defective' proteins in brain cells.

Patrik Verstreken (VIB/KU Leuven): "These unexpected results offer us a new line of approach for research into communication between brain cells. We feel that in time it should be possible to help patients with mutations in the TBC1D24 gene, by partially inhibiting transport to the lysosomes (compartments in the cell that digest various molecules)."

A good model for the study of neurodegenerative diseases

We know that mutations in the TBC1D24 gene cause a brain disorder that brings with it conditions including extensive , epilepsy, mental retardation and hearing problems. Patrik Verstreken and his colleagues have developed fruit flies with mutations in the Skywalker gene, the fruit fly version of TBC1D24. These fruit flies display similar symptoms to patients with brain disorders.

Patrik Verstreken explains: "These fruit flies are not only a suitable model for investigating what goes wrong in the brain, but also for exploring how this can be tackled. For instance we are attempting to reduce or eliminate the symptoms in the with mutations in Skywalker by introducing further changes to their DNA. If successful, it means that we have new starting points for our research into neurodegeneration."

Need for "contaminated, defective" proteins

Brain cells communicate with one another at a synapse. Ana Clara Fernandes, Valerie Uytterhoeven and their colleagues, led by Patrik Verstreken, were screening for genes with a potential impact on communication between brain cells. In the process they came across HOPS complex genes. The HOPS complex ensures that contaminated, defective proteins at the synapse (where communicate with one another) are transported to the lysosome, the compartment of the cell responsible for breaking down the proteins.

When the VIB researchers cut out half of the HOPS complex genes in their fruit fly model for neurodegeneration, the flies were found to be no longer ill. Initially this seems rather strange, because a less active HOPS complex means that the transport of defective proteins to the degradation site is not working as well as it should. This research has shown, however, that defective proteins also play a role at the synapse. These surprising results offer a new line of approach for research into brain disorders.


Explore further

Over-activity of enzyme HDAC6 exacerbates symptoms of Amyotrophic Lateral Sclerosis

Citation: Has a possible new lead been found in the fight against neurodegenerative diseases? (2014, November 24) retrieved 19 July 2019 from https://medicalxpress.com/news/2014-11-neurodegenerative-diseases.html
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.
 shares

Feedback to editors

User comments

JVK
Nov 25, 2014
Excerpt: "...we are attempting to reduce or eliminate the symptoms in the fruit flies with mutations in Skywalker by introducing further changes to their DNA. If successful, it means that we have new starting points for our research into neurodegeneration."

Apparently, researchers realize the importance of an atoms to ecosystems approach that incorporates what is known about the role of RNA-mediated events and amino acid substitutions in neurotransmission. Introducing what would typically be the result from more RNA-mediated changes that led to stability of DNA in organized genomes via amino acid substitutions is addressed in:

Excitatory amino acid transporters: recent insights into molecular mechanisms, novel modes of modulation and new therapeutic possibilities http://www.scienc...14001362

See the "of outstanding interest" context added to the bibliography and recommended reading.

JVK
Nov 25, 2014
cont.

"The thermodynamics of Na+ and substrate binding to cross-linked double cysteine-mutants of GltPh trapped in outward-facing and inward-facing conformations are investigated at using ITC and fluorescence-based assays. Na+ binding to the transporter is found to induce a site capable of substrate binding and undergoing subsequent conformational transitions. Thus, cation binding and unbinding events are the driving force of the EAAT transport cycle".

Thermodynamic stability at the level of molecular epigenetics linked to amino acid substitutions and organism-level thermoregulation involves levels of complexity that theorists have typically attributed to beneficial mutations. Supposedly, the beneficial mutations are somehow selected and manifested in the DNA of organized genomes.

However, what we see here attests to the fact that biophysical constraints should be included in evolutionary theories, lest they appear to be utterly ridiculous.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more