Intracellular transport mechanisms might play a vital role in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a disease that attacks the nervous system, rapidly destroying the patient's motor neurons.
The illness begins with muscle weakness; at first, symptoms are subtle, patients might stumble or slur their speech.
Gradually, the weakness worsens and moves to the muscles that control breathing, eventually leading to death.
Life expectancy is normally just 3-4 years and only 10% survive longer than a decade from diagnosis. There are 5,600 new diagnoses made in America each year but, to date, no cure is forthcoming.
In 90-95% of cases, the cause of ALS is not known. However, over recent years, a genetic component has been uncovered, with a number of mutations found to crop up in affected individuals.
Researchers, led by Dr. Robert H. Baloh of Cedars-Sinai in Los Angeles, CA, decided to look in depth at one of these genes, known as C9orf72.
The role of C9orf72 in ALS
C9orf72 was the first gene to be linked to ALS and is also known to play a role in frontotemporal dementia, another neurological disease without a cure.
A mutation in C9orf72 is known to be present in around 40% of familial cases of ALS and up to 10% of sporadic, non-familial cases. This makes the gene the most commonly found mutation in relation to ALS.
The role of C9orf72 in healthy individuals is not fully known, but it is thought to play a role in endosomal trafficking - a vital cellular mechanism responsible for the transport of molecules in and around cells.
In order to unpick the role of C9orf72 in ALS, Dr. Baloh and his team bred mice who lacked the gene in question. But, rather than the mouse developing ALS, they displayed immune system dysfunction.
Modified mice and lysosome failure
The team found that the lysosomes in the genetically modified mice had stopped functioning correctly. Lysosomes are found in nearly all animal cells. They are, in basic terms, tiny, acidic packets containing a cocktail of enzymes. They break down proteins, fats, cellular debris and other material.
The lysosome's role as the garbage collector of the cell has earned them the charming nickname "suicide bags." This title belies their vital role in cellular homeostasis; they play an integral part in repairing the plasma membrane, cell signaling and energy metabolism.
This surprising alteration in the mice confirms a strong relationship between ALS and the immune system. Immune abnormalities and inflammation have previously been noted in ALS, but it was not clear whether these were the body's response to the disease or part of the disease itself.
This new evidence shows that, in fact, the immune system's role might be key to understanding the etiology of ALS. As Dr. Baloh says:
"The C9orf72 gene is critical for the function of immune cells in the brain, adding to growing evidence that the brain's immune system actively contributes to disease rather than simply responding to injury."
The future of amyotrophic lateral sclerosis
The team hopes that the findings might lead to better treatment, especially for patients who carry the C9orf72 gene mutation.
The results also infer that any drug designed to reduce levels of the mutated C9orf72 might have the potential to further disrupt the delicate processes of the immune system and must be approached with caution.
The gene studied in these experiments is not the only one implicated in ALS. Medical News Today asked Dr. Baloh if other known mutations might have similar immune roles. He said:
"We suspect that other ALS genes, particularly those involved in similar processes to C9orf72 such as TBK1, OPTN, p62, etc., all potentially could lead to a faulty immune response."
The normal role of C9orf72 and the protein it codes for is still relatively unclear. Some researchers believe they might be involved in the activation of Rab proteins. These proteins are also part of the intricate logistics of transporting compounds within cells.
MNT asked Dr. Baloh whether Rab proteins might be of future use in the treatment of ALS: "It is definitely possible that drugs targeting Rabs, or drugs targeting other regulators of Rab function could be useful therapeutically," he replied.
Although a successful treatment for ALS is a long way off, we are slowly unlocking its secrets. Dr. Baloh plans to continue his work in this area; he told MNT that he will be investigating "evidence of altered immune function in C9orf72 patients and whether other ALS genes have a similar effect."
MNT recently covered research into protein clumps thought to play an important role in ALS.