25th of  June 2019

De Neuro D-generation and the art of zooming out 

While some fight ALS, others Parkinson’s and others Multiple Sclerosis, the reality is our fights are all linked. Researchers believe that if we can discover a cure to one of these neurodegenerative diseases, we can help find cures for all. Few, however, know that our fights are linked. It’s time to change that – I Am ALS

Last week, patient advocates Justine FedakBenjamin Stecher and Brian Wallach joined forces/voices in what I would like to call the “Neuro D-generation”: A patient-led movement that wants to break down artificial walls between neurodegenerative diseases, to speed up discovery and to find a cure for all.

Neurodegenerative disease is an umbrella term for complex multisystem diseases which – sooner or later – lead to the breakdown and death of neurons in the Central Nervous System (the brain and spinal cord together). The process of degradation may lead to a loss in motor neuron functions, impaired sensory abilities, a decline in memory and cognitive abilities along with hindrances in the functioning of – and eventual failure of – organ systems.

MS, ALS and Parkinson’s

Justine suffers from MS, Brian from ALS and Benjamin from Parkinson’s. All three diseases have a profound influence on the ability to exert control over our muscles. In the illustrations below, you see the effect of MS and ALS on our motor neurons.

MS

In MS, motor neurons are losing their protective, insulating shell: myelin. This process is called demyelination. The loss of myelin hinders the neurons from transferring electrical impulses to and from the brain. You can compare this effect with an electrical wire without insulation: the signal transmission is disrupted and a short circuit may occur. The sites where myelin is lost appear as hardened scar tissue. MS stands for Multiple Sclerosis, which means ‘many scars’.

ALS

In ALS, Amyotrophic Lateral Sclerosis, motor neurons progressively weaken. A (none) myo (muscle) trophic (nutrition) means: no nutrition for muscles. Muscles do not receive sufficient nerve impulses. Muscles that aren’t excited, decrease in mass and eventually disappear. Lateral indicates the area in the spinal cord where the weakening nerve cells are located. If the nerve cells in this area die, this leads to hardened scar tissue: Sclerosis.

Parkinson’s

The inter-disease galaxy

In scientific literature, the connection between neurodegenerative diseases such as ALS, Alzheimer, Frontotemporal dementia, Huntington’s, MS and Parkinson’s is readily acknowledged. Inflammation supposedly is one of the factors which contributes to all neurodegenerative disorders. Not only neuroinflammation (e.g. Brambilla, 2019, Voet, 2019). Chronic intestinal inflammation (e.g. Serra, 2019) is also implicated.

The borders between the diseases aren’t as strict as our language suggests. For example, in literature, we see similar disease mechanisms and characteristics such as:

All neurodegenerative diseases show the formation of misfolded protein aggregates in – or between – degenerating neurons (e.g. see George, 2017, David, 2014, Ramesh, 2017).

Astrocytes (also called astroglia) are non-neuronal cells which provide for the maintenance of our neurons. They are going rogue across neurodegenerative diseases (e.g. Bennet, 2019, Liddelow, 2017a and 2017b).

In Parkinson’s, dopaminergic neurons in the substantia nigra die, but other areas of the brain may also be affected. For example, both in Parkinson’s as well as in ALS, serotonin dysfunction is implied, probably due to lesioning of the raphe nuclei (Vermeiren, 2018).

Research into neurodegeneration reports changes in mitochondrial function (E.g. Cowan, 2018). Mitochondria are known as the power houses of our cells but they also have other important functions in the signaling cascades within our neuronal cells.

The art of zooming out (and in) 

The initiative of IAmALs to connect research galaxies from a patient perspective is very inspiring to me. Currently, patient associations are more or less working in silos. Zooming out to a shared research agenda may prove to be essential in a major challenge of our time: understanding and curing neurodegenerative diseases.

At the moment, we assign someone fairly coarsely to a specific neurodegenerative disease. And within that broad classification, almost no patient feels 100% seen. Ultimately, it is in the individual differences (between but also within diseases) that disease manifests itself. Each patient needs his or her own, tailor-made, treatment and cure. This seems to be a statement which suggests an opposite movement than that of IAmALS: We should zoom in more! But that is only true if you know what you need to zoom in on. And well, that is precisely where our current knowledge isn’t conclusive and our understanding falls short.

So it may sound contradictory, but it isn’t: Zooming out makes zooming in possible.

The good news is: Zooming out is happening! Major investigations are currently being conducted to collect as much data as possible from the patient. In the Parkinson op Maat study, for example, data is collected from patients 23 hours a day. If such datasets are made available as FAIR open data, then datasets from different diseases will be able to “talk” to each other. By linking datasets, we can open up the inter-disease data galaxy for questioning from all kinds of unthought angles. And then … the art of zooming in will take its turn.

When in doubt, zoom out | Reggie Watts

Sparks

Sources

Bennett, J. P., Keeney, P. M., & Brohawn, D. G. (2019). RNA Sequencing Reveals Small and Variable Contributions of Infectious Agents to Transcriptomes of Postmortem Nervous Tissues From Amyotrophic Lateral Sclerosis, Alzheimer’s Disease and Parkinson’s Disease Subjects, and Increased Expression of Genes From Disease-Activated Microglia. Frontiers in Neuroscience13https://doi.org/10.3389/fnins.2019.00235 (Open Access)

Brambilla, R. (2019). Neuroinflammation, the thread connecting neurological disease. Acta Neuropathologica137(5), 689–691. https://doi.org/10.1007/s00401-019-02009-9 (Open Access)

Cowan, K., Anichtchik, O., Luo, S. (2018). Mitochondrial integrity in neurodegeneration. CNS Neuroscience and Therapeutics, Jul;25(7):825-836. https://doi.org/10.1111/cns.13105(Open Access)

David, M. A., & Tayebi, M. (2014b). Detection of Protein Aggregates in Brain and Cerebrospinal Fluid Derived from Multiple Sclerosis Patients. Frontiers in Neurology5https://doi.org/10.3389/fneur.2014.00251 (Open Access)

George, S., & Brundin, P. (2017). Solving the conundrum of insoluble protein aggregates. The Lancet Neurology16(4), 258–259. https://doi.org/10.1016/s1474-4422(17)30045-5 (Closed Access)

Kumar Singh, R., Satapathy, S., Singh, A., & Bhuyan, K. (2016). Implication of Epigenetic Modifications in Neurodegenerative Disorders: Traces and Imprints. Journal of Clinical & Cellular Immunology7(5). https://doi.org/10.4172/2155-9899.1000461 (Open Access)

Liddelow, S. A., & Barres, B. A. (2017a). Reactive Astrocytes: Production, Function, and Therapeutic Potential. Immunity46(6), 957–967. https://doi.org/10.1016/j.immuni.2017.06.006 (Open Access)

Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Barres, B. A. (2017b). Neurotoxic reactive astrocytes are induced by activated microglia. Nature541(7638), 481–487. https://doi.org/10.1038/nature21029 (Closed Access)

Ramesh, N., & Pandey, U. B. (2017). Autophagy Dysregulation in ALS: When Protein Aggregates Get Out of Hand. Frontiers in Molecular Neuroscience10https://doi.org/10.3389/fnmol.2017.00263 (Open Access)

Serra, D., Almeida, L. M., & Dinis, T. C. P. (2019). The Impact of Chronic Intestinal Inflammation on Brain Disorders: the Microbiota-Gut-Brain Axis. Molecular Neurobiologyhttps://doi.org/10.1007/s12035-019-1572-8 (Closed Access)

Vermeiren, Y., Janssens, J., Van Dam, D., & De Deyn, P. P. (2018). Serotonergic Dysfunction in Amyotrophic Lateral Sclerosis and Parkinson’s Disease: Similar Mechanisms, Dissimilar Outcomes. Frontiers in Neuroscience12https://doi.org/10.3389/fnins.2018.00185 (Open Access)

Voet, S., Srinivasan, S., Lamkanfi, M., & Van Loo, G. (2019). Inflammasomes in neuroinflammatory and neurodegenerative diseases. EMBO Molecular Medicine11(6). https://doi.org/10.15252/emmm.201810248 (Open Access)

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