Hopkins finds link in Lou Gehrig’s and dementia

At first glance, there seems to be almost no connection between Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD), two neurological disorders. However, a team of researchers at Johns Hopkins University School of Medicine recently found that these frightening disorders may share the same cause.

When affected by ALS, also known as Lou Gehrig’s disease, patients first experience rapid weakening and stiffening of muscle groups. They often have difficulty swallowing or report weakness in their arms, and muscle functions continue to deteriorate as the disease progresses.

In contrast, when patients present with FTD, they undergo a progressive breakdown of certain cognitive abilities, such as the ability to focus, exhibit proper social conduct or complete basic behavioral tasks. For example, a patient suffering from FTD might pick up an empty glass and seriously attempt to drink the absent liquid. Led by Jiou Wang, Assistant Professor of biochemistry, molecular biology and neuroscience at the Johns Hopkins School of Medicine, the researchers traced the biological history of both diseases. They found a common origin in a particular mutation of C9orf72, a gene located on the ninth human chromosome.

The mutated version of C9orf72 features a series of repeats in its genetic code. Unlike cancer-causing mutations, this mutation occurs in a section of the gene that does not encode for anything related to functions of the human body. Nevertheless, the mutation causes the genes to bind together into a three-dimensional structure the researchers have called the Hexonucleotide Repeat Expansion (HRE). After more investigation, Wang and his team determined that these HREs are the culprits behind ALS and FTD.

It was discovered that HREs led to abnormal functioning of the nucleic acids in neurons of the human body. When RNA molecules, short-living duplicates of DNA responsible for transmission of genetic information in cells, are constructed from C9orf72 genes, HREs block them from carrying out their proper functions. As a result, large numbers of these incomplete RNA molecules, referred to as the G-quadruplex, are produced and circulate freely within the cell.

Coincidentally, the G-quadruplexes are structured in such a way that they bind tightly to a number of proteins that normally circulate in the cell. One such protein is the nucleotin. In a normal human neuron cell, nucleotin is concentrated in certain regions of the cell. In a diseased cell of an ALS patient, however, nucleotin is scattered throughout the cell. According to Wang, this suggests that the HREs may impair important functions of RNA-binding proteins in human neurons.

Research into the mutation of C9orf72 will continue. Wang and his team think, in addition to causing the formation of HRE and the G-quadruplex, the C9orf72 mutation may have significant detrimental effects on important functions within the human neuron. Although more research is needed, this discovery sheds light on a new disease-causing interaction that may pave the way for innovative ALS and FTD therapy.