Biology subjects

McAllen, R.

Publications and source records attributed to McAllen, R..

3 recordsLinked to original sources

bioRxiv2026

Schwann Cell-Specific TDP-43 Rescue Improves Peripheral Nerve Myelin Pathology Without Altering Motor Behaviour in a Mouse Model of ALS

Amyotrophic lateral sclerosis (ALS) is a terminal disease caused by motor neuron loss. Schwann cells, the myelinating cells of the peripheral nervous system, metabolically and structurally support neurons. ALS patients exhibit Schwann cell pathology, such as TDP-43 proteinopathy, therefore Schwann cell dysfunction may contribute to disease progression. Here, we have characterised myelinating Schwann cell pathology in a TDP-43Q331K (TDP-43) transgenic mouse model of ALS. We also crossed the floxxed TDP-43 mouse with a myelin protein zero (P0)-cre mouse to excise the transgene from Schwann cells alone (P0-cre/TDP-43) to assess rescue. Compared to wild-type (WT) littermates, 10 mo TDP-43 mice exhibited changes to myelin architecture, including loss of myelin binding proteins at the paranodes, decreased node of Ranvier length, and non-compact, degenerating myelin. In P0-cre/TDP-43 mice these myelin disruptions were rescued. However, this improved histology did not lead to a functional rescue, with both P0-cre/TDP-43 and TDP-43 mice exhibiting slowed sciatic nerve conduction and worsened motor behaviour. Further histological analyses revealed that Bungner Schwann cells, a subtype of Schwann cells triggered by neuronal injury, were activated in both TDP-43 and P0-cre/TDP-43 mice. Activation of Bungner Schwann cells can trigger damaging inflammation through the recruitment of macrophages, which can hinder motor and electrophysiological performance, potentially underpinning the lack of functional rescue in the P0-cre/TDP-43. We established that the rescue of Schwann cells indeed protects myelin in this ALS model, however understanding how Bungner Schwann cells exacerbate neuronal pathology is essential for developing effective therapeutics that can improve functional output. Significance StatementAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure and limited treatments. Given that the average patient life expectancy is 3-5 years following diagnosis, finding novel treatment targets is of the utmost importance. Recent research has revealed that non-neuronal cells, such as Schwann cells, contribute to the disease, however the extent of their pathology remains elusive. Investigating Schwann cell and peripheral myelin pathology in ALS may lead to the identification of previously unrecognized disease mechanisms, opening novel avenues for therapeutic development. Identifying approaches through which to target glial and neuronal pathology concurrently would enable more holistic treatment of the various aspects of ALS pathobiology to improve patient outcomes.

neuroscience↗

bioRxiv2023

Transcriptomic responses of sponge holobionts to in situ, seasonal anoxia and hypoxia

Deoxygenation can be fatal for many marine animals; however, some sponge species are tolerant of hypoxia and anoxia. Indeed, two sponge species, Eurypon sp. 2 and Hymeraphia stellifera, survive seasonal anoxia for months at a time. To understand their tolerance mechanisms, we performed differential gene expression analyses on the sponges, their mitochondria and their microbial symbionts under in situ conditions of normoxia, hypoxia and anoxia. Each species possessed a unique microbiome, but the microbiomes of each species were dominated by a species-specific Thaumarchaeon and a Gammaproteobacterium. Holobiont gene expression was species-and oxygen-level dependent, though there were some shared interspecific responses to deoxygenation. In general, few changes occurred in the expression of sponge metabolic genes as a function of oxygenation level, indicating that they may remain metabolically active under anoxia. However, ATP synthesis genes were significantly upregulated under hypoxia when compared to normoxia, and genes for DNA replication were downregulated. Mitochondrial gene expression was effectively unchanged under both hypoxia and anoxia. Nevertheless, both anoxia and hypoxia caused upregulation of heat shock proteins (HSPs), indicating cellular level adaptations to deoxygenation stress. A meta-analysis demonstrated that sponge transcriptional responses to anoxia were distinct from those displayed by other invertebrates while dormant, and the hypothesis of sponge dormancy under anoxia was not supported. Thaumarchaeota symbionts also upregulated stress response genes in hypoxia, while maintaining expression of oxygen-dependent metabolic pathways under hypoxia and anoxia. Gammaproteobacteria symbionts showed relatively few noteworthy changes in gene expression in response to anoxia but decreased metabolic gene expression in hypoxia. There was no clear evidence of upregulated anaerobic respiration in the transcriptomes of the sponge holobionts under anoxia or hypoxia. The tolerance of some sponges to prolonged anoxia warrants further investigation and could give them an advantage in future oceans following climate change as well as in ancient oceans when oxygen concentrations were lower than at present.

ecology↗

bioRxiv2020

The effects of seasonal anoxia on the microbial community structure in demosponges in a marine lake (Lough Hyne, Ireland)

Climate change is expanding marine oxygen minimum zones (OMZs), while anthropogenic nutrient input depletes oxygen concentrations locally. The effects of deoxygenation on animals are generally detrimental; however, some sponges (Porifera) exhibit hypoxic and anoxic tolerance through currently unknown mechanisms. Sponges harbor highly specific microbiomes, which can include microbes with anaerobic capabilities. Sponge-microbe symbioses must also have persisted through multiple anoxic/hypoxic periods throughout Earth history. Since sponges lack key components of the hypoxia-inducible factor (HIF) pathway responsible for hypoxic responses in other animals, it was hypothesized that sponge tolerance to deoxygenation may be facilitated by its microbiome. To test this hypothesis, we determined the microbial composition of sponge species tolerating seasonal anoxia and hypoxia in situ in a semi-enclosed marine lake, using 16S rRNA amplicon sequencing. We discovered a high degree of cryptic diversity among sponge species tolerating seasonal deoxygenation, including at least nine encrusting species of the orders Axinellida and Poecilosclerida. Despite significant changes in microbial community structure in the water, sponge microbiomes were species specific and remarkably stable under varied oxygen conditions, though some symbiont sharing occurred under anoxia. At least three symbiont combinations, all including large populations of Thaumarchaeota, corresponded with deoxygenation tolerance, and some combinations were shared between distantly related hosts. We propose hypothetical host-symbiont interactions following deoxygenation that could confer deoxygenation tolerance. ImportanceThe oceans have an uncertain future due to anthropogenic stressors and an uncertain past that is becoming clearer with advances in biogeochemistry. Both past and future oceans were, or will be, deoxygenated compared to present conditions. Studying how sponges and their associated microbes tolerate deoxygenation provides insights into future marine ecosystems. Moreover, sponges form the earliest branch of the animal evolutionary tree and they likely resemble some of the first animals. We determined the effects of variable environmental oxygen concentrations on the microbial communities of several demosponge species during seasonal anoxia in the field. Our results indicate that anoxic tolerance in some sponges may depend on their symbionts, but anoxic tolerance was not universal in sponges. Therefore, some sponge species could likely outcompete benthic organisms like corals in future, reduced-oxygen ecosystems. Our results support the molecular evidence that sponges and other animals have a Neoproterozoic origin, and that animal evolution was not limited by low-oxygen conditions.

microbiology↗