Publication highlights

As ALS involves disruption to RNA-binding proteins, which coordinate the movement and metabolism of genetic messages called RNAs, researchers at the Crick and UCL investigated how changes to an RNA-binding protein called SFPQ could underpin some of the disease pathology. They identified an alternative version of the SFPQ protein, which is found in a different cellular location compared to the regular SFPQ protein. The team then found that ALS-affected cells are more likely to produce and use the alternative SFPQ protein rather than the regular one, which mirrors findings in ALS patient tissues that SFPQ is often found in abnormal places in the cell. Finally, they showed that the alternative SFPQ has different behaviour and function, which may underlie hallmarks of the disease in ALS-affected cells. This work suggests that correcting levels of alternative SFPQ might alleviate some of the negative downstream consequences for RNA molecules and ultimately damage to nerve cells in ALS.

Researchers at the Francis Crick Institute and UCL have shown that hundreds of proteins and mRNA molecules are found in the wrong place in nerve cells affected by Motor Neuron Disease (MND), also known as Amyotrophic Lateral Sclerosis (ALS).

ALS is a rapidly progressing and devastating condition that causes paralysis by affecting motor neurons, with limited treatment options. Until now, scientists were aware that a few proteins, especially a protein called TDP-43, were found in unexpected locations in ALS nerve cells.

But new research published today in Neuron shows that the problem is much broader. This ‘mislocalisation’ affects many more proteins than first thought, especially those involved in RNA binding. The mislocalisation extends to mRNAs too, molecules that deliver instructions to make proteins from the DNA in the nucleus.

Remarkably, the mislocalisation of proteins and mRNAs was partially improved with a drug called ML240, which blocks the action of the VCP enzyme. Blocking this enzyme also led to other beneficial effects on cell function, such as reducing the level of damage to DNA.

Amyotrophic lateral sclerosis (ALS), also known as Motor Neuron Disease, is a devastating neurological disease that causes motor neurons to die, leading to muscle weakness and ultimately death. It has been challenging to access motor neurons to identify the underlying causes of the disease, due to high risk of complications that come with a biopsy of the fragile spinal cord. Researchers have turned to studying motor neurons derived from induced pluripotent stem cells (iPSC) to better understand ALS. However, previous iPSC studies were limited to small numbers of patients, and there is no consensus on how ALS develops.

In this study, researchers combined iPSC-derived motor neurons and post-mortem spinal cord tissue data into a large resource, to identify changes that cause motor neuron death in ALS. They found that ALS leads to an accumulation of somatic mutations and a heightened DNA damage response. Although these changes were observed in various types of ALS, they were most notable in cases where the nuclear protein, TDP-43, was relocated to the cytoplasm. This study highlights genome instability as a hallmark of ALS and could help in the development of new therapies.

Researchers in the Rickie Patani lab have revealed cell autonomous harmful changes in supporting cells, called astrocytes, in Amyotrophic Lateral Sclerosis (ALS). They found that astrocytes with different ALS-causing genetic mutations also have distinct underlying molecular patterns. This suggests that, during ALS, astrocytes themselves acquire significant mutation-dependent changes.