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Journal Reviews

Posted in Journal Reviews on 10th Dec 2012

Epha4 inhibition suggests axonal therapies may be useful for ALS

ALS is a clinically heterogenous disease, and genetic factors probably explain much of its variation, including the variable age of onset and disease duration (even within families with heritable ALS). Identifying these factors may tell us how we may be able to manipulate the disease, allowing us to delay onset or slow progression, and thus lead to effective therapies. Van Hoecke et al have recently made a significant step forward in this respect. Their work is an excellent example of the kind of scientifically holistic, collaborative approach needed if we are ever to crack the tough nut that is neurodegeneration.

Van Hoecke and colleagues started with zebrafish expressing ALS-associated mutant SOD1G93A. The embryonic fish have short, aberrantly branching motor axons. They then used a hypothesis-free approach: a genetic screen. With no a priori assumptions they left open the possibility of identifying entirely new molecular pathways relevant to disease. This is the beauty and power of the ‘forward screen’ approach.

They performed their screen by randomly knocking down zebrafish genes using morpholinos (synthetic oligonucleotides, which possess conventional bases, but whose backbones are made of morpholine rings rather than deoxyribose rings). From a library of just 303 genes, knockdown of 13 genes was found to result in improvements in axon degeneration. Knock down of Rtk2 in particular completely reversed axonal abnormalities. As we now know that ALS is a TDP-43 proteinopathy, another important experiment Van Hoecke et al conducted was to use transgenic zebrafish expressing ALS-linked mutant TDP-43. Indeed, the axons of these fish were also rescued by knockdown of Rtk2 expression.

Van Hoecke et al make no comment on the gross motor phenotype or survival of these fish, but this is not the point of their study (they were not trying to cure fish). Instead, their next key step was to move up to mammals to examine the Rtk2 homologue, Epha4. Mutant SOD1 transgenic mice were crossed with mice expressing only half the normal amount of Epha4. Reducing the expression of Epha4 significantly increased the motor performance and survival of SOD1G93A mice, and increased the number of motor neurones seen in the spinal cord. Furthermore, SOD1G93A rats treated with an Epha4 inhibiting peptide had delayed disease onset.

The team went further, turning their attention to patients with ALS. While no genetic association was found with SNPs surrounding the Epha4 locus and ALS susceptibility or phenotype, an association was found when measuring blood Epha4 mRNA levels. Lower expression of Epha4 was correlated with later disease onset and prolonged disease duration. Furthermore, two Epha4 gene mutations (both disrupting Epha4 function) were found in one sporadic and one familial ALS patient. Intriguingly, both patients had very long disease durations (the fALS patient is still alive after 12y).

Epha4 is a receptor for ephrins, a family of proteins involved in axon repulsion during development. In the context of neurodegeneration, ephrins may also have a role in adults, playing a role in synapse formation, plasticity and memory. In this respect, it is interesting to note that Van Hoecke found that mice with half the normal expression of Epha4 had an increased ability to reinnervate muscle following experimental injury of the sciatic nerve. This observation adds further weight to the hypothesis of ‘dying back’ as a critical process in ALS pathogenesis, with degeneration starting peripherally in the axon and nerve terminal and working retrogradely to the cell body. The challenge now is to break down the molecular mechanisms by which Epha4 is involved in motor axon degeneration and determine if any of these pathways can be targeted for therapy. – Jemeen Sreedharan, Dept of Neurobiology/ Neurology, University of Massachusetts Medical School, 364 Plantation St, Worcester, MA 01605, US.
Van Hoecke A, et al. EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans.
NATURE MEDICINE. 2012 Aug 26. doi: 10.1038/nm.2901.

Brain injury and homelessness, the chicken and the egg

Who are the homeless? Is being homeless a state through which one passes, temporarily? Is homelessness an outcome measure? Following hard on the heels of recent work that has demonstrated an increased prevalence of traumatic brain injury (TBI) amongst the prison population, this survey attempts to shine a similar light upon the homeless. Obviously the homeless, like the prison population are a relatively easily defined group if viewed at a particular point in time and place. The circumstances that would lead one to be without a house or residing at Her Majesty’s pleasure are however rather more complex than, perhaps, these surveys would hope to suggest. The implication here is that if the homeless were screened for cognitive problems arising from traumatic brain injury then the provision of “appropriate and useful support” may be possible. A sample of homeless individuals attending hostels in Leeds were asked a series of questions around their recollection of having sustained a brain injury (along with it’s severity) and their answers compared with a sample of people “on the streets of Leeds” (who presumably had homes to go to). Unfortunately, the information regarding prior acquisition of a TBI was based on individual recall, although differentiation of severity depending on loss of consciousness was considered. Lifetime prevalence of TBI amongst the homeless was 48% compared with 21% for the non-homeless. A large proportion (90%) of those who were homeless and had sustained a TBI had done so prior to being homeless.

In an ideal world then, perhaps we could prevent homelessness by screening everyone sustaining a brain injury and then giving them the support and guidance that they need. Unfortunately this is almost certainly going to be much more complicated. Alcohol, illicit drug use, parental support, the availability of social housing, mental illness, education and employment are all potential factors in the precipitation and the perpetuation of homelessness. By definition “homelessness” is heavily dependent upon particular environmental factors that are not biologically modifiable. But, as surrogate a measure as this is, the state of being homeless is perhaps more meaningful than a dry score on an abstract cognitive assessment. Are homeless people more likely to sustain TBIs than they would, otherwise? Is this relevant?  Perhaps the precipitation and perpetuation of homelessness are not easily delineated and we need to think beyond a simple causal relationship. – Lloyd Bradley, Consultant in Rehabilitation Medicine, Western Sussex Hospitals Trust.
Oddy M, Moir J F, Fortescue D, Chadwick S. The Prevalence of traumatic brain injury in the homeless community in a UK city.
BRAIN INJURY 2012;26(9):1058-64.

What are you laughing at?

What constitutes “humour” differs greatly between different individuals and groups. Disability-related humour presents a challenge. There is the risk of going beyond being flat or unamusing to becoming offensive. One would like to imagine that comedy has progressed in its level of sophistication such that disability-related humour is more about mining seams of absurdity and laughing at prejudice rather than enforcing it.

This paper reiterates that the attitude of the public, particularly employers, towards people with disabilities is potentially more handicapping than the disabilities themselves.  One of the only consistent factors that has been identified in fostering positive attitudes towards people with disabilities is previous contact in work, educational and social settings. Specific training to promote awareness and positively influence employers’ attitudes has been rolled out, but any of us unfortunate enough to be corralled into a yearly “diversity awareness training workshop” will appreciate that these are not always as useful as they might be.

So why not try to use humour as a means of promoting attitude change? The central question is whether the use of disability-related humour would be more effective than provision of information, alone. To this end, a group of undergraduate business students and therefore (by extension) future employers were shown a short film; either Laughing at our Differences or Without Pity: A Film About Abilities. The former is a stand-up comedy routine by an individual with a lower limb amputation consisting of “humorous stories about his experiences as a person with a disability”. The latter a documentary about the lives of 3 different individuals with different impairments and their coping strategies. The students were assigned to watch the humorous film, the serious film or no film and then complete the ATDP (apparently the Attitudes Towards Disabled People) scale. There is a small but significant correlation in positive attitudes and viewing the humorous film. Interestingly, the sample that viewed the serious film had a (non significantly) less positive attitude afterwards. The authors suggest, therefore, that disability humour may be a means of positively influencing attitudes towards persons with disability.

Humour does not lend itself to close scrutiny. The social, temporal and personal factors involved are too inscrutable for even the most factor-controlling quantitative analysis. There is nothing more toe-curling than something supposedly comedic that falls flat and given how culturally specific a lot of American stand-up comedy is, the message is likely to be lost on many audience members. The authors suggest that other research to address the types of disability related humour that evoke the most positive attitudes is required. Perhaps a slapstick vs satire cross-over? Or a deadpan vs one-liners case series?

It would be interesting to look at the effect on attitudes across the population as a whole following the potentially enhanced visibility of persons with disabilities in the context of the Paralympic games, as one senses that the “us” engendered by sporting participation may change more minds than a man telling jokes about the travails of life with one leg. – Lloyd Bradley, Consultant in Rehabilitation Medicine, Western Sussex Hospitals Trust.
Smedema SM, Ebener D, Grist-Gordon V. The impact of humorous media on attitudes towards persons with disabilities.
DISABILITY AND REHABILITATION 2012;34(17):1431-7.

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