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Gene research sheds new light on ALS

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Despite short repetitive DNA sequences having been linked to numerous neurodegenerative diseases, our understanding of the mechanisms that underlie their pathology has remained in its infancy. Dr Haeusler’s research investigating the first sequence repeat to be linked to ALS-linked diseases has uncovered the core mechanism through which the mutation results in cellular damage.

Although the Human Genome Project deciphered the human DNA sequence about fifteen years ago, our understanding of the function of all that is encoded in the sequence remains far from complete. Dr Aaron Haeusler, an Assistant Professor in the new Jefferson Weinberg ALS Center in the Vickie and Jack Farber Institute for Neuroscience at Thomas Jefferson University in Philadelphia, is investigating a specific region of the human genetic sequence. This region varies greatly in size between individuals and has been linked to numerous neurodegenerative diseases. His work is beginning to unravel the mechanisms by which the expansion of short repetitive DNA sequences can result in disease.

Urgent Need to Discover ALS Cure
Haeusler’s research thus far has focused primarily on investigating the association between these sequences and amyotrophic lateral sclerosis (ALS). The symptoms of ALS, also known as Lou Gehrig’s disease and motor neurone disease, result from the death of neurones responsible for controlling voluntary muscle movement. The condition is degenerative with progressive motor neurone loss, which manifests as stiff and twitching muscles with increasing weakness and atrophy, leading to the eventual loss of control of all voluntary movement. There is currently no known cure for ALS and any applicable therapies only extend life by a few months, with assisted ventilation providing some further therapeutic value. The progression of the disease, which usually begins between the age of 50 to 60, is rapid with an average survival from onset of only three to four years.

cellDr Haeusler has been investigating a region of DNA that encodes a gene within chromosome 9, open reading frame 72, known as C9orf72. When mutations occur in this portion of DNA code, it can result in varying numbers of repeats of a part of the sequence. This gene mutation was the first of this type to be linked to neurological disease and since being described, a number of clinically distinct disorders have been associated with this genetic defect.

There is currently no known cure for ALS and any applicable
therapies only extend life by a few months Quote_brain

Unravelling the Role of Repeating DNA Sequences
This repeating region of sequence is known as a nucleotide repeat expansion (NRE). When less than 30 repeats are present this does not usually result in any problems. However, the NRE in the gene can contain hundreds to thousands of repeats in individuals. This type of high-number repeat has been identified as the most common genetic abnormality in patients with ALS and frontotemporal dementia (FTD). Similarly, other neurological and neuromuscular disorders have also been linked to the expansion of short repetitive DNA sequences. These include NRE-linked Fragile X, Huntington’s, Alzheimer’s disease and many ataxias.

C9orf72 NRE ALS Model_3.4Although the short repeating sequence has been linked to many diseases, the primary mechanism by which this type of mutation results in those conditions has remained unclear. This has hindered the development of therapeutic interventions that could prevent disease progression. However, while working in Dr Jiou Wang’s laboratory as a postdoctoral fellow, Dr Haeusler, in collaboration with other Johns Hopkins ALS laboratories, recently identified mechanisms that may account for the neurotoxicity seen in ALS patients due to the NRE of C9orf72.

Cellular Disruption on Several Levels
Collaborations between laboratories at Johns Hopkins, involving Drs Jeffrey Rothstein, Tom Lloyd, and Jiou Wang, studied drosophila, a type of fruit fly commonly used as a model organism in genetic research. They also employed C9orf72 ALS patient brain tissue and neurones derived from stem cells and brain tissue of C9orf72 ALS patients. A focused genetic screen for proteins associated with suppression of neurodegeneration identified a drosophila homologue of a human gene and protein it encodes, known as RanGAP1. This protein is a key regulator of transport between the cell nucleus and the cytoplasm. Their study showed that when C9orf72 DNA is transcribed into RNA, the RNA structures that are formed are also expanded, which collapse in on themselves forming abnormal three-dimensional structures. The C9orf72 RNA that results from the NRE mutation interacts with RanGAP1 and transport between the nucleus and cytoplasm is perturbed. It is possible that direct interactions between nuclear transport complexes and the RNA cause this disruption in C9orf72 expressing flies, C9-ALS patient-derived neuronal cells, and brain tissue.

In addition to this, they found that the resulting RNA structures may also interfere with the activity of other components of the nuclear pore complex. These structures are the channels through which transport of molecules between the nucleus and cell cytoplasm occurs. Therefore, disruption of their activity leads to dysfunctional transport. This collaborative research effort involving Dr Haeusler concluded that it is this disruption of transport at nuclear pore complexes that is a fundamental mechanism for induction of cellular injury in not only ALS but also FTD in C9orf72 repeat-expansion patients. Dr Haeusler hypothesises that this may also be one of the primary causes of the cellular defects associated with other neurodegenerative diseases. He also speculates that similar nuclear transport dysfunction may be responsible for age-related neurodegeneration in healthy individuals, since it has come to light that many nuclear pore complex components are very long lived and the integrity of these complexes may be compromised as ageing progresses.

Rescuing Neuronal Cells Destined for Destruction
Importantly, they also demonstrated that the deficits in nuclear transport resulting from the C9 mutation could be rescued in both the fly model and cultured human neurones. This was demonstrated by using molecules targeted at the abnormal RNA produced from the mutated DNA sequence. Therefore, molecules such as these show great potential in attenuating the defects in nuclear trafficking that occurs in the cells of patients with this mutation.

Dr Haeusler postulates that, as the current human genome is filled with repeat DNA sequences with a high degree of variation between individuals, NREs similar to those of C9orf72 may underlie many other diseases. Identifying these regions and understanding the mechanisms by which they result in disease is therefore essential for the future development of treatments. Dr Haeusler envisions that we are ’at the tip of the iceberg in understanding how repetitive DNA sequences function in normal biology and contribute to human disease’. In the Jefferson Weinberg ALS Center at Thomas Jefferson University, he aims to further expand on our knowledge of the mechanisms by which NREs such as those in C9orf72 result in human disease and to identify therapeutic targets for intervention.

What led you to focus your research on the C9orf72 repeating sequence in particular?
My PhD work focused on the dynamics of nucleic acid protein complexes in the context of genetic regulation. I wanted to extend this work into disease models, and I was drawn to nucleotide repeat expansion diseases and ALS, which converged with the discovery of the C9orf72 mutation in ALS and FTD.

Why do you think research looking at repetitive DNA sequences has been so limited, despite there being so many of these regions in the human genome?
Unfortunately, it can be technically difficult to sequence through highly-repetitive DNA regions. Furthermore, most sequencing technological approaches rely on aligning relatively short DNA reads that may not span the entire repeat region. Therefore, if the repeat region was long enough, we could be unable to read through and properly assemble the entire region due to the redundancy of the sequence and the inability to stitch the short reads of DNA sequence back together correctly.

How far away do you think we are from having effective therapies available for ALS and other neurodegenerative diseases that can attenuate the pathology of the C9orf72 NRE?
It only takes one great scientific breakthrough to find a cure. However, it is difficult to put a time on when this will occur. I believe the ALS field has made substantial progress in understanding disease-linked mechanisms recently, and the discovery of the C9orf72 gene has been truly exciting in an already invigorated field of research. Importantly, the advancements we have made in understanding different mechanisms of ALS, have also revealed that there may not be a single cure for all of ALS, but rather akin to the cancer field, specialised treatment regimens to combat specific patient symptoms within the observed disease spectrum or stage of ALS.

What has been the most exciting finding you have been part of during your career in research so far?
I was really glad to be a part of the great work coming out of exploring nucleocytoplasmic transport defects. I think with this discovery we are on the cusp of greater discoveries and new potential therapeutic strategies. However, I think the most exciting findings are still to come.

Are there any other avenues you plan to pursue with your research in the following years in relation to NREs?
I am fascinated by NRE expansions in disease, and we have learned a lot about the C9orf72 NRE paradigm through the excellent mechanistic work that has accumulated over the years by studying other NRE-linked diseases such as Fragile X, Huntington’s, Myotonic dystrophies, and many of the spinal cerebellar ataxias. Proceeding forward I will look at these prototypical NREs to understand how the C9orf72 NRE compares.

Research Objectives
Dr Haeusler’s research focuses on neurodegeneration linked to repeating sections of DNA. His work is directly relevant to the pathogenesis of Amyotrophic Lateral Sclerosis (ALS) and related ageing-dependent chronic neurological disorders.

National Institutes of Health (NIH)


  • Christopher Donnelly, PhD, University of Pittsburgh
  • Jiou Wang, PhD, Johns Hopkins University
  • Jeffrey Rothstein, MD, PhD, Johns Hopkins University
  • Tom Lloyd, MD, PhD, Johns Hopkins University
  • Davide Trotti, PhD, Thomas Jefferson University
  • Piera Pasinelli, PhD, Thomas Jefferson University

haeusler-aaronAaron Haeusler obtained a BS in Biochemistry from Northern Michigan University before attending graduate school under the guidance of his PhD advisor, Jason D Kahn, PhD at the University of Maryland, College Park. A postdoctoral fellow with his mentor, Jiou Wang, PhD followed at Johns Hopkins University, Bloomberg School of Public Health in Baltimore. His work here brought him to his current home in the new Jefferson Weinberg ALS Center at Thomas Jefferson University.

Dr Aaron Haeusler, PhD
Assistant Professor
Jefferson Weinberg ALS Center
Vickie & Jack Farber Institute for Neuroscience
Department of Neuroscience
Thomas Jefferson University
900 Walnut Street, JHN – Suite 410
Philadelphia, PA 19107

T: +1 215 955-8630

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