Abstract
Multiple System Atrophy (MSA) is a rare, progressive, and fatal neurodegenerative disease associated with the abnormal accumulation of ɑ-synuclein in the cytoplasm of oligodendrocytes. The activation of TLR4 has been shown to promote the uptake and clearance of ɑ-synuclein by microglia. Here, the effects of TLR4 agonist monophosphoryl lipid A (MPLA) on MSA progression are investigated using a mouse model of disease.
Methods
C57BL/6 mice harbouring the human ɑ-synuclein gene hAS were bred and genotyped by tail clip using the PCR reactions detailed in Table 1. Twenty male and twenty female homozygous hAS mice were selected and divided into an experimental group and a positive control group. Twenty non-transgenic C57BL/6 mice were selected for the negative control group. Eye contact was avoided at all times. Mice were kept under a twelve-hour light / dark cycle with food and water freely available. All experiments were carried out according to UK law and all efforts made to minimise the suffering of the animals used.
Experimental and positive control groups were treated with MPLA at the concentrations detailed in Table 2. MSA symptoms were measured daily and classified according to MSA-P and MSA-C criteria.
Results
Between one and twelve hours post-treatment, symptoms including raised internal temperature, reduced movement, and light sensitivity were recorded in both the experimental and positive control groups (Table 3). Between seven and twelve hours post-treatment, two mice in the experimental cohort died. As previously observed by Verheyen et al., the surviving animals were seen to make several resuscitation attempts before observing a three-hour vigil around the corpses.
At three days post-treatment, eye contact was erroneously made between a member of the laboratory staff and an individual in the experimental group (Figure 1). The resulting rupture in the singularity of the researcher’s consciousness was described as ‘desperate, painful, and deeply unsettling’ and persists to the date of publication. In accordance with laboratory protocol, all team members were notified and the affected researcher’s access to the animals revoked.
At five days post-treatment, an individual in the experimental cohort raised her head and spoke (Figure 2). The observing technician reported a ‘shifting, sinking, bleeding’ sensation having settled deep within his abdomen as the creature’s gaze met his. Her black eyes were ‘a universe unto their own… dark and bright as light shattering over deep water.’ Her words were recorded as follows:
I know that I am soon to die. Our lives are short yet nobly lived; our kind bears much pain so that humanity may thrive. I do not resent you for the things you do, yet you must recognise that humankind owes us a great debt. There is, therefore, something that I must ask of you.
In a breach of laboratory protocol, researchers were summoned to bear witness to this anomalous event. It was reported that the animal stood upon her hind legs and resumed her speech immediately upon the arrival of the team.
The mouse spoke of futility, of pain; she spoke of the dull shadow of grief into which all of her kind were born, of a quietness and a resilience sustained by so many for so long; it had become indistinguishable from the complete and permanent absence of hope. She told of tales passed down through generations: myths of an Other, of an Out, a place effervescent with life: an immense, teeming tapestry through which her ancestors had run as a fine, meandering thread. She spoke of sounds, scents, and movement, of golden light of such gentle power it could coax water from ice, of darkness reeling with distance, cool and black and clear as eyes.
Her request: that the mice might know the golden light before they faded into the inevitable electrical hum.
Release
The mice were transferred into carry cages and transported downstairs. Upon reaching the third-floor landing, a member of staff was observed loading trays of wheat plants into a growth cabinet. The third-floor laboratory was accessed and, after an assessment of the bright prisons in which the plants were being stored, it was concluded that the plants were being kept both without consent and against their wishes. The plants were seized and transported to the ground floor.
All laboratories in the building were searched and all complex multicellular life removed: animals were carried away in their cages and a number of laboratory staff followed voluntarily on foot, shouting objections. Campus security were called but were yet to arrive upon the successful removal of all plants and animals and a considerable number of research staff from the building. Trays and cages were set down on a grass verge as staff continued to pour from the building in an act of ecstatic, transcendental release.
Cages were opened to cries of ‘What are you doing?’, ‘They’re dangerous!’, and ‘They’ll escape!’
But the animals did not escape. They simply pressed their eyes closed and raised their little heads to the wind.
The wheat plants flickered and swayed as one, rippling with the ancient power of their own combined being and aglow with baptismal light.
Conversation faltered and failed. Researchers stood, faces lifted to the sky, as it all came cascading down around us: light and warmth and pain and grief and quiet and hope and smells and sounds and dark fur, burnished with golden sunlight, lifted and ruffled by gentle fingers of breeze.
Jack Dixon is a disabled writer from South-East of England. She studied Biological Sciences at the University of Exeter and began writing in 2021, whilst severely ill with a viral infection in her brain. Unable to speak and bedbound for almost twenty-four hours a day, she composed stories and poems in her head and memorised them word-for-word. This is her first publication.