Motor neurones are very long, complex cells, and it is likely that their death in MND is caused by attacks from multiple sources. Researchers are working hard to defend motor neurones ‘from all sides’ and, to do this, they need to know the neurones’ weaknesses.
They believe there are two ways in which motor neurones are attacked. Firstly, proteins are moving out of the control centre of the cell (the nucleus) and into the area around the nucleus (the cytoplasm) and clumping together there. Secondly, they believe that the support cells that should protect the neurones ‘go wrong’ and instead of protecting, they start attacking the neurones.
If you look at a motor neurone affected by MND down the microscope, you’ll see clumps of proteins. But how did those proteins get there? These proteins are the wrong shape, as they have clumped together, and are in the wrong part of the cell, the cytoplasm, instead of the central nucleus. Clues on how they are getting there are found by studying an inherited form of MND, for example the one caused by mutations in the C9orf72 gene.
To get through to the cytoplasm from the nucleus, the proteins need to cross the equivalent of a city wall. They do this by passing through controlled ‘gateways’. Some researchers are looking at these gateways and how they are controlled and also the structure of the gateways themselves. The proteins have important jobs to do in the cell nucleus to keep motor neurones healthy and functioning well. Their movement into other parts of the cell, and staying there in clumps, could be one of the reasons why motor neurones die. If the gateways can be kept secure, structurally sound and work properly, that may slow down MND.
The following presentations will discuss RNA-binding proteins and transport at the Symposium. Find their abstracts using the codes below in Abstracts online:
- C11: RNA-binding proteins and nucleocytoplasmic transport defects in ALS.
- C12: The nuclear pore complex is compromised in SALS and ALS/FTD.
- C13: Safety and efficacy of SRSF1-dependent nuclear export inhibition of C9orf72 repeat-transcripts: moving towards therapies.
- C14: Phase separation of FUS is suppressed by the nuclear import receptor transporting and FUS arginine methylation.
Researchers are also looking at what happens when the cells that support motor neurones ‘go wrong’. Motor neurones are surrounded by support cells called glial cells. In MND, something happens to change them and they appear to attack the motor neurones instead of protecting them.
Two particular support cells have been studied the most in MND. These are called microglia and astrocytes. Microglia help protect motor neurones from damage and injury. Astrocytes have more of a role in supporting the health of neurones. How they do this, however, is less well understood.
Researchers have developed different ways to learn about microglia. This includes (a) learning about microglia activity using a brain scan ‘live tracker’, (b)how blocking attack by microglia can increase the lifespan of mice with MND, and (c) how microglia can help reduce the effects of MND by clearing away dead motor neurones.
Motor neurones will grow quite happily on their own in a dish in the lab. However, if astrocytes are grown in the same dish, or motor neurones are grown in liquid that has previously contained astrocytes, the motor neurones die. This suggests that astrocytes are passing something toxic onto the motor neurones.
A team of researchers has been looking at what causes this in more detail. They took skin cells from healthy people and from people with the C9orf72 inherited form of MND. They used these to create astrocytes in the lab using stem cell technology. Stem cells are cells that have not yet been given a function and can turn into any type of cell. They particularly looked at what healthy astrocytes are passing on compared to the astrocytes in people with MND. They have found two factors that may be causing the toxicity which may become a target for future therapies.
The following presentations will discuss support cells and their effect on MND at the Symposium. Find their abstracts using the codes below in Abstracts online:
- C82: Imaging glial activation in people with ALS.
- C84: Slowing disease progression in the SOD1 mouse model of ALS by blocking neuregulin-induced microglial activation
- C85: The role of microglia in TDP-43 clearance and redistribution in the zebrafish spinal cord.
- C83: MicroRNAs secreted by C9orf72 patient-derived astrocytes contribute to impairment in axonal growth and cell death in vitro