Remember me if you forget your name: ALS and FTLD

7 Nov 2016. NUS biologist is part of the team that have discovered an important step in the development of ALS (amyotrophic lateral sclerosis), a neurodegenerative disease that is fatal.

You may have heard about recent worldwide fund-raising attempts for ALS research, involving several celebrities, known as “the ALS challenge”. ALS, also known as motor neuron disease or Lou Gehrig’s disease, is named after the great American baseball player Henry Louis Gehrig, who was affected by it, which subsequently led to the identification of this disease. The potential root cause of this neurodegenerative disease that causes non-functionality of voluntary muscles is now identified. The affected person lives normally until 30 or 40 years of age, but suddenly develops non-functional voluntary muscles. These muscles control virtually all every day activities, like walking, lifting, eating etc. In most ALS cases, the associated fronto-temporal lobar degeneration (FTLD) makes people forget things. Slowly, the affected person becomes unable to do anything physically, leading to a fatal end.

During his sabbatical with Prof Ramin SHIEKHATTAR at the Wistar Institute, Philadelphia, USA, Prof Kunchithapadam SWAMINATHAN from the Department of Biological Sciences, NUS started working on the root cause of ALS and FTLD. These neurodegenerative diseases stem from a genetic disorder. In a normal person, the C9ORF72 gene is expressed and this produces the corresponding protein in motor neuron brain cells (which control voluntary muscles). This protein forms a complex (with other proteins) that is involved in the autophagy (recycling and digestion) of all unwanted cellular components in the motor neuron, keeping it functional. In an ALS/FTLD patient, this gene has an unexpected number of repeats (say about 1,500, whereas a normal person has only about two or three) of the sequence “GGGGCC” in the promoter region. This abnormality causes reduced production of the associated C9ORF72 protein and the “cleaning” complex. The environment in the motor neuron becomes “dirty”, leading to the failure of motor neuron brain cells to issue the correct orders to muscles.

Currently, there is no cure for ALS/FTLD. The connection between the disease and the C9ORF72 gene was discovered only a couple of years ago. Autophagy is essential for cellular stability because it removes and recycles unwanted cellular components. It also provides energy to the cell. Even though its role has been discovered in ALS, FTLD, Parkinson’s, Alzheimer’s, and Huntington’s disease, no detailed mechanism has been proposed for ALS.

The present work (and publication) is an important step in elucidating the role of autophagy in ALS. While several groups are working on this topic, these results provide an important area for further detailed research towards the cure of ALS. While DNA sequence analysis could identify the disposition of an individual to ALS, no cure is available for this deadly disease. Their findings could lead to the development of treatment strategies.

While the reason for the development of ALS, in light of C9ORF72 and autophagy, is emerging, the detailed mechanism of the onset of this disease is still elusive. There are still several unanswered questions. Does the genetic composition of a patient predispose him to ALS or are there any changes in his genomes after birth? How does the patient live until 30 or 40 years of age without developing the disease? Why does a person develop this disease and what are the activators? Is there any other mechanism involved in suppressing the C9ORF72 expression? What are the structural answers for protein-protein interaction of C9ORF72 and other partners? Prof Swaminathan is continuing further research to answer some of these questions.

Figure shows the recycling (autophagy) of unwanted cellular components in brain motor neuron cells is orchestrated by a complex formed by C9ORF72 and associated proteins. In ALS patients, C9ORF72 and the recycling complex is missing, leading to waste material accumulation and non-functional motor-neuron cells, resulting in a lack of muscular activity.

Reference

Yang M; Liang C*; Swaminathan K; Herrlinger S; Lai F*; Shiekhattar R*; Chen JF, “A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy” SCIENCE ADVANCES Volume: 2 Number: 9 Article Number: e1601167 DOI: 10.1126/sciadv.1601167 Published: 2016