Most neurology meetings have a tried and true, if somewhat shopworn, format: every 15 minutes, another speaker delivers another five-minute introduction to the field, then presents five minutes of new results, then answers five minutes of questions. Next speaker.
Hiroshi Mitsumoto, MD, the Wesley J. Howe Professor of Neurology at Columbia University and director of the Neuromuscular Division, had a different idea for an amyotrophic lateral sclerosis (ALS) meeting he organized recently in Tarrytown, NY — one he likened to “speed chess.” What if each speaker was given three minutes at most to present his or her main idea, and then took questions for 20 minutes or more? And what if speakers, who included both basic scientists and clinicians, were asked to be provocative, to shake things up, and to try to find new angles on the pathogenesis of this difficult disease?
During the course of the three-day meeting, a new ALS gene was announced, a new paradigm for the spread of neurodegenerative disease was promoted, and a “new universe” of RNA-based epigenetics was discussed — all with implications for understanding ALS and its treatment.
DR. HIROSHI MITSUMOTO said that one proposal for understanding the pathogenic diversity presumed to underlie ALS is to focus on the clinical subtypes of motor neuron disease seen in every ALS clinic, including upper versus lower motor neuron predominance, bulbar versus limb onset, progressive muscular atrophy, ALS with or without dementia, and other phenotypes.
Mark F. Mehler, MD, professor and chair of neurology at Albert Einstein University in New York, who led the epigenetics discussion, said: “The meeting was an amazing success. There were dozens and dozens of talks, and we heard the actual kernel of substance in each one. I think we are now going to be referring to the ‘Mitsumoto method’ of meeting organization.”
A new star emerged in the growing constellation of ALS genes, announced by Teepu Siddique, MD, professor of neurology at Northwestern University Feinberg School of Medicine in Chicago, who led a consortium that discovered gene mutations in patients with X-linked ALS and ALS/dementia. The gene, called UBQLN2, encodes the protein ubiquilin 2, which regulates protein degradation, and the mutations they discovered impaired this function. The protein aggregates in the brains and spinal cords of patients with UBQLN2 mutations, but also in those with other genetic and sporadic forms of the disease, suggesting that dysfunction of ubiquilin 2 may link multiple forms of ALS. The discovery places ALS squarely on the growing list of neurodegenerative diseases in which defects of protein degradation likely contribute to pathogenesis.
The new discovery, plus the recently announced chromosome 9 open reading frame 72 gene (C9ORF72) brings the total number of ALS genes to more than a dozen. The sporadic form, which still accounts for the lion's share of the disease, may itself be due to multiple initial causes. The likely conclusion is that ALS is not a single disease, but a syndrome. So the question is whether and where all these different pathways converge.
John Trojanowski, MD, PhD, co-director of the Center for Neurodegenerative Disease Research at the University of Pennsylvania, proposed a possible convergence point in the spread of protein aggregates from cell to cell. He stressed that there was not yet evidence for this process in ALS, but there was reason to think it is likely.
DR. JOHN TROJANOWSKI: “No one has done this yet, but I would speculate that if we took brain lysates from ALS patients or TDP43 mutant mice, we may be able to transmit the disease.”
“There is a precedent for transmission” in Parkinson disease and Alzheimer disease, which have patterns of spread through the nervous system that are highly suggestive of cell-to-cell transmission of pathology, he said. Extracts of mouse brain with amyloid or tau pathology can induce that pathology in healthy brain, and his collaborator, Virginia Lee, PhD, has recently demonstrated that purified alpha-synuclein can be taken up by neurons and trigger formation of protein aggregates reminiscent of Lewy bodies.
He pointed out that most forms of ALS, including sporadic disease, are characterized by aggregates containing large amounts of TAR DNA binding protein-43(TDP43). “No one has done this yet, but I would speculate that if we took brain lysates from ALS patients or TDP43 mutant mice, we may be able to transmit the disease.”
Dr. Trojanowski's lab is working on just this experiment now. He also noted that to date, no one has done this kind of careful autopsy work in ALS that established the pattern of spread in Parkinson disease and Alzheimer disease, “in part because until 2006, when we discovered TDP43, there was no pathological fibril to follow.” Initial work now shows that even in ALS patients whose clinical features are purely motor, TDP43 pathology can be found elsewhere in the brain.
“My statement to the group was, this could be how ALS progresses once it develops. We think this cell-to-cell spread of neurodegeneration is a whole new, radical concept of the mechanism of these diseases.”
DR. MARK F. MEHLER: “ALS is probably the first neurodegenerative disease in which so much evidence is pointing to abnormalities in RNA metabolism. By understanding the gene networks involved, this new epigenetic science will allow us to target single processes with a certainty never before possible.”
And that concept has important implications for therapy. “If the pathology spreads, you could nip this in the bud with antibodies that penetrate the brain and snag the pathogen in flight from one cell to another.”
Perhaps the most provocative presentation of the meeting was by Dr. Mehler. Dr. Mehler studies epigenetics, a field that may do for biomedicine in the twenty-first century what genetics did for it in the twentieth. And if what Dr. Mehler proposes is right, much of what we think we know about the genetics of disease is wrong.
The “old” epigenetics focused on chromosome modifications — histone modifications and methylation — that affected gene function, which are relatively long-lived in the life of the cell. But in the past few years, with the development of tools to track the moment-to-moment flux in RNA within an active cell, it has become clear that at every moment, hundreds to thousands of short-lived RNA molecules are being transcribed from DNA, none of which encode proteins, but instead appear to play brief but important roles in regulating expression of hundreds of genes. “Compared to the twenty thousand protein-coding genes, there is evidence for at least a million independent noncoding RNA species. And it may turn out there may be ten to twenty million,” Dr. Mehler said. “It's staggering.”
What's more, the DNA sequence of a single protein often overlaps with the sequence of hundreds of regulatory RNAs. “For fifty years we thought when we mutated a base pair, we changed one protein.” Instead, because of the effect on all the RNAs encoded at the same site, “you could be altering huge gene networks across the entire genome, with hundreds of genes involved in a multitude of biological functions,” he said. “For the first time this begins to give us a clue that the complex genotype of a neurological disease may not be caused by a single protein that malfunctions. The site you mutate may be the epicenter of a whole noncoding RNA universe.”
The implications for ALS are potentially profound. “ALS is probably the first neurodegenerative disease in which so much evidence is pointing to abnormalities in RNA metabolism. By understanding the gene networks involved, this new epigenetic science will allow us to target single processes with a certainty never before possible.”
DR. BRYAN TRAYNOR: “I am quite sure that regulatory RNA networks are going to be important, and will explain some portion of disease. But does it negate everything that we've learned about the genetics of neurodegenerative disease to date? No. But science moves forward by people having the guts to pursue new ideas to the nth degree.”
Bryan Traynor, MD, co-discoverer of the C9ORF72 gene and an investigator at the National Institute on Aging, commented to Neurology Today: “I am quite sure that regulatory RNA networks are going to be important, and will explain some portion of disease. But does it negate everything that we've learned about the genetics of neurodegenerative disease to date? No. But science moves forward by people having the guts to pursue new ideas to the nth degree.”
Dr. Mitsumoto called this glimpse of the new epigenetics “wonderful.” “Genetics is complicated enough to me, but he is talking about a new universe. There is so much complexity. Once more, we need to expand our horizons.”
Dr. Mitsumoto noted that one proposal for understanding the pathogenic diversity presumed to underlie ALS is to focus on the clinical subtypes of motor neuron disease seen in every ALS clinic, including upper versus lower motor neuron predominance, bulbar versus limb onset, progressive muscular atrophy, ALS with or without dementia, and other phenotypes.
“Some people think this is the key to understanding the disease,” Dr. Mitsumoto said. It is unknown whether riluzole, for instance, is more effective in one type of patient versus another. Clinical trials that enroll all types may miss a phenotype-specific effect, leading to abandonment of a useful drug.
“I am a clinician,” said Dr. Mitsumoto. “Clinicians need to focus on these areas to help basic scientists find the cause.” Becoming involved in ALS clinical research consortia, and encouraging patients to enroll in clinical trials, are key steps to making progress, he said.