Variability in human axon survival

Axons are the long 'wires' that link one nerve cell to another. They are one of the first structures to be lost in almost all degenerative disorders of our brains, spinal cords and nerves. The consequences include pain, disability, loss of memory, hearing and sight in disorders such as Alzheimer's disease, motor neuron disease and multiple sclerosis. Peripheral neuropathies, disorders affecting the network of nerves outside the central nervous system, often resulting from diabetes or the side effects of cancer chemotherapy, are one example of an axonal disorder. Glaucoma, resulting from disruption of the optic nerve by pressure in the eye, is another.

There are two main ways to study axon degeneration. One is in animal or cell culture models. These model systems bring major advantages for research, for example the underlying molecular mechanism can be studied in ways that would not be possible in humans, and drugs can be tested without risk to people. However, these models often do not fully represent the corresponding human disease. They are valid because we share much of our DNA sequence and most types of cells with other mammals, but there are always some limitations.

The second, highly complementary approach is human genetics. Methods for sequencing and analysing human DNA have improved dramatically since the human genome was first sequenced and this is revolutionising our understanding of which genes may cause or contribute to common and rare disorders. However, ultimately these results are correlation rather than proof. Experimental model systems, such as those described above, are needed to extend this research.

By studying axon degeneration in mouse, cell culture and fly models, we have made substantial progress in understanding an important axon degeneration mechanism. Animal models of disease have helped us understand its potential role in human disease and in normal ageing, the single biggest risk factor for many neurodegenerative disorders. Developments in human genetics have independently suggested that the proteins regulating axon degeneration in these model systems play a role in human disease, and generated far more data on how these proteins differ within the human population. The essential next steps are to understand how variations in these proteins within the human population can affect normal protein function, so we will make similar changes in animals or cell culture models to test whether features of the corresponding human diseases emerge. Based on our knowledge of the pathway in mice we are also able to test whether blocking this pathway in various ways can prevent disease.

This work takes important steps towards translating years of progress in axon degeneration in model systems into real understanding of how the pathway malfunctions in human disease and hence towards therapies that can prevent or treat disease.

We study the pathway of axon degeneration after injury: Wallerian degeneration. Data from animal models suggest related mechanisms influence axon survival in some diseases and in ageing, including multiple sclerosis (MS), peripheral neuropathies (PN), glaucoma and some motor neuron diseases. Early axon loss is also prominent in Alzheimer's disease, Parkinson's disease and ALS. There are no disease-modifying therapies. Here, we address the role of this pathway in human axon survival.

Mutations of five genes are now known to robustly delay Wallerian degeneration in mice and other model organisms but whether a similar phenotype exists in humans has remained an intriguing but unanswered question. Recent GWAS and exome linkage between Wallerian pathway genes and ALS and a painful neuropathy, and animal studies, suggest that such a phenotype could function as a disease modifier. SNP databases indicate polymorphisms likely to delay Wallerian degeneration and others likely to confer an opposite phenotype of axon vulnerability. Our mouse and preliminary human studies support this notion.

We will test which human variants alter axon survival by testing their function in mouse neurons that lack the homologous mouse gene. Using established assays, we will ask whether human variants in a pro-survival protein, NMNAT2, support axon survival and if so how strongly, and whether variants in human SARM1, a pro-degenerative protein, restore rapid Wallerian degeneration when mouse SARM1 is missing. We will then estimate the prevalence of these phenotypes. We will test whether NMNAT2 deficiency is a risk factor for neuropathic pain, and having shown that SARM1 deletion completely rescues nerve growth and early lethality in NMNAT2 null mice, we will test whether it also rescues a premature age-related decline that we find in mice expressing low levels of NMNAT2. These data will complement ongoing GWAS and exome studies to understand the roles of this pathway in human disease.

The potential non-academic beneficiaries of this project are:
(1) Pharma/biotech companies targeting neurodegenerative disorders where axon degeneration plays an important role. In particular, the move towards personalized medicine will benefit from the type of functional data we will generate. Through our Workshop organization we will also help to stimulate similar work elsewhere resulting in indirect benefit to similar companies. Axon degeneration is a significant event in most neurodegenerative diseases, including some which are highly prevalent and therefore represent major market opportunities for the commercial sector: Alzheimer's disease (lifetime risk 15%), stroke (15%), diabetic neuropathy (7%), glaucoma (2%) and Parkinson's disease (1.5%). There are no disease-modifying treatments. As explained in 'pathways to impact' we will actively engage the commercial sector to ensure this potential is realized, for example through our ongoing CASE studentship with Takeda (Cambridge).
(2) Patients with neurodegenerative disorders and their families. Understanding the genetic basis of disease is crucial. Substantial progress is being made in GWAS and exome studies but functional characterization such as we will carry out (and further stimulate through our Workshop) is vital for knowing which genes are actually causing or contributing to disease and therefore represent the right drug targets. As an increasing component of human disease is recognized to reflect genetic makeup, offering relatives the option to know whether they too are at risk will become more important. While this has important ethical considerations too, moving forward on the technological ability to do this in this work will be an important step.
(3) Lay public interested in nervous system function. In our public engagement activities we find a strong interest in the nervous system among the lay public. While there is only a limited amount that individuals can do about the health of their nervous system, understanding what goes wrong can at least help some patients to come to terms with it, and motivates some healthy individuals to ensure they avoid a lifestyle that places strains on axon survival (e.g., excessive alcohol consumption, obesity, drug abuse).