Publication highlights

The amount of any given protein in a cell has to be controlled to keep its levels within a range required for healthy functions, which is especially important for proteins that group together in condensates which generally contain flexible parts and can form many interactions at the same time. Aiming to discover how the cell regulates the amounts of these proteins, researchers at the Crick and King's College London's UK Dementia Research Institute investigated nuclear speckles, condensates in the nucleus, discovering a new way for cells to maintain the equilibrium of many proteins that condense together. They termed this 'interstasis': how the accumulation of various proteins in a condensate can decrease further production of the same proteins by capturing their own mRNAs (messenger molecules) into the same condensate. In this way the cell can regulate genes that are particularly dose-dependent and proteins which are involved in many diseases of ageing.

Abnormal movement of the RNA-binding protein TDP-43 from the nucleus to the cytoplasm in vulnerable brain cells is a hallmark of motor neuron disease. Losing the function of TDP-43 in the nucleus causes genetic sequences called ‘cryptic exons’ to be erroneously included in mature RNA transcripts. While these have been detected before, most of these events were predicted to produce faulty instructions that would be discarded. Whether or not these events translate into new proteins has remained an open question.

By removing TDP-43 in human stem cells grown in the lab, the researchers at the Crick, UCL and NIH discovered 65 new small proteins called ‘cryptic peptides’ which are produced when TDP-43 is lost from the nucleus. They detected 18 of these new proteins in cerebrospinal fluid samples from people with ALS or FTD. This discovery opens the door for both an exciting new fluid biomarker of disease progression in ALS/FTD and the intriguing possibility of cryptic peptides triggering an autoimmune response in disease.

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.