All forms of ALS are caused by a protein recycling system in the neurons of the spinal cord and brain that breaks down. For neurons to function properly, they rely on the effective recycling of the protein building blocks in cells – they need to be removed and reprocessed. In ALS, when the recycling system is broken, the cells cannot repair themselves, resulting in serious damage.

This breakthrough has been published in the journal Nature, and was authored by scientists from Northwestern University Feinberg School of Medicine.

ALS (amyotrophic lateral sclerosis), also known as Lou Gehrig’s disease or motor neuron disease, is a fatal neurodegenerative illness that paralyzes patients. For scientists, the development of effective medications and therapies has been impossible, because the underlying process of the disease has been an enigma. In fact, many wondered whether ALS’ different forms actually formed part of a common disease process.

This new discovery provides scientists with a shared target for drug therapy. The authors wrote that “All types of ALS are, indeed, tributaries, pouring into a common river of cellular incompetence.”

Senior author, Teepu Siddique, M.D., said:

“This opens up a whole new field for finding an effective treatment for ALS. We can now test for drugs that would regulate this protein pathway or optimize it, so it functions as it should in a normal state.”

The protein recycling breakdown discovery may help find new therapies for other neurodegenerative diseases as well, the authors add, including Alzheimer’s disease and Parkinson’s disease, both of which are characterized by the accumulation of proteins.

Siddique wrote that for the proper functioning of cells, damaged or misfolded proteins have to be removed and reprocessed.

In all three forms of ALS, the authors say the breakdown occurs. The three forms are called familial ALS (hereditary), sporadic ALS (not hereditary), and ALS/dementia (targets the brain).

The researchers also identified a new gene mutation which is present in ALS/Dementia and familial ALS, further linking the two forms of the disease.

Siddique, who has been researching the causes and underlying mechanisms of ALS for over 25 years, said he was fascinated by the subject because:

“It was one of the most difficult problems in neurology and the most devastating, a disease without any treatment or known cause.”

Approximately 350,000 people globally are affected by ALS. About half of all patients die within three years of onset. In the motor disease, the patient gradually loses muscle strength until he/she cannot move, swallow or breathe. With ALS/dementia, the frontal and temporal lobes are affected, the patient gradually loses judgment, and eventually cannot understand language or perform basic tasks, such as organizing their day or planning what clothes to put on.

Siddique said:

“These people in the prime of their lives and the peak of their productivity get this devastating illness that kills them. The people who get ALS/dementia, an even more vicious disease, have a double whammy.”

The scientists discovered ubiquilin2, a protein that is key to recycling misfolded or damaged proteins in cortical and motor neurons.

Ubiquilin2 is not doing what it should in patients with ALS. Consequently, the ubiquilin2 remains and the damaged proteins build up in the motor neurons in the cortical and hippocampal neurons in the brain, as well as the motor neurons in the spinal cord. The protein build-up looks like twisted skeins of yarn (typical ALS characteristic), and cause the neurons to degenerate.

The scientists found ubiquilin2 in the brain of ALS/dementia patients as well as in the spinal cords of ALS cases.

They also found ubiquilin2 mutations in cases of familial and familial ALS/dementia.

The skein-like build-ups were identified in the spinal cords and brains of all ALS and ALS/dementia patients, regardless of whether or not they had the gene mutation.

Senior author, Han-Xiang Deng, M.D., said:

“This study provides robust evidence showing a defect in the protein degradation pathway causes neurodegenerative disease. Abnormality in protein degradation has been suspected, but there was little direct evidence before this study.”

The majority of ALS cases are sporadic (90%), and until this study, without any known cause. Approximately 10% are familial. So far, 10 gene mutations have been identified, including SOD1 and ALSIN.

Written by Christian Nordqvist