Biology subjects

Martins, R. R.

Publications and source records attributed to Martins, R. R..

4 recordsLinked to original sources

bioRxiv2024

M102, a combined NRF2 and HSF-1 activator for neuroprotection in amyotrophic lateral sclerosis.

M102 is a central nervous system (CNS) penetrant small molecule electrophile which activates in vivo the NFE2-related factor 2 antioxidant response element (NRF2-ARE) pathway, as well as transcription of heat-shock element (HSE) associated genes. In the TDP-43Q331K transgenic mouse model of ALS dosed subcutaneously at 5mg/kg OD or 2.5mg/kg BD with M102, significant improvements in compound muscle action potential (CMAP) amplitude of hind limb muscles and gait parameters were observed at 6 months of age, with associated target engagement. An oral dose response study of M102 in SOD1G93A transgenic mice showed a dose-dependent improvement in the CMAP of hindlimb muscles which correlated with preservation of lumbar spinal motor neurons at the same time point. These data enabled prediction of human efficacious exposures and doses, which were well within the safety margin predicted from Good Laboratory Practice (GLP) toxicology studies. A parallel program of work in vitro showed that M102 rescued motor neuron survival in co-culture with patient-derived astrocytes from sporadic, C9orf72 and SOD1 cases. Markers of oxidative stress, as well as indices of TDP-43 proteinopathy were also reduced by exposure to M102 in these in vitro models. This comprehensive package of preclinical efficacy data across two mouse models as well as patient-derived astrocyte toxicity assays, provides a strong rationale for clinical evaluation of M102 in ALS patients. Combined with the development of target engagement biomarkers and the completed preclinical toxicology package, a clear translational pathway to testing in ALS patients has been developed. One Sentence SummaryM102, a dual NRF2/HSF1 activator, slows disease progression in 2 mouse models and exerts neuroprotection in human cellular models of ALS.

neuroscience↗

bioRxiv2022

TRANSCRIPTOMIC SIGNATURES OF TELOMERASE-DEPENDENT AND -INDEPENDENT AGEING, IN THE ZEBRAFISH GUT AND BRAIN

Decreased telomerase expression, telomere shortening, senescence-associated markers and inflammation have all been independently observed in the ageing brain and associated with disease. However, causality between limited telomerase expression and brain senescence and neuro-inflammation in the natural ageing setting is yet to be established. Here, we address these questions using the zebrafish as an ageing model which. Akin to humans, zebrafish display premature ageing and death in the absence of telomerase and where telomere shortening is a driver of cellular senescence. Our work shows for the first time that telomerase deficiency (tert-/-) accelerates key hallmarks of ageing identified in the Wild Type (WT) zebrafish brain at transcriptional, cellular, tissue and functional levels. We show that telomerase depletion accelerates ageing-associated transcriptomic changes associated with dysregulation of stress response and immune genes. These are accompanied by accelerated in situ accumulation of senescence-associated markers and inflammation in the aged brain. Importantly, In vivo, these changes correlate with increased blood-brain barrier permeability and increased anxiety-like behaviour. Of note, the acceleration of senescence-associated markers in the absence of tert occurs not only in the expected proliferative areas but also in non-proliferative ones, where it is unlikely due to telomere-dependent replicative exhaustion, suggesting that non-canonical roles of telomerase may be involved. Together, our work suggests that telomerase has a protective role in the zebrafish brain against the accumulation of senescence and neuro-inflammation and is required for blood-brain barrier integrity. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/493215v4_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@12d3171org.highwire.dtl.DTLVardef@8f45eorg.highwire.dtl.DTLVardef@1e37580org.highwire.dtl.DTLVardef@372777_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract Telomerase depletion accelerates markers of ageing in the zebrafish brain, ranging from dysregulated immune and stress ageing transcriptomic hallmarks to in situ accumulation of senescence-associated markers and inflammation, dysfunction of the blood-brain barrier and increased anxiety behaviour. C_FIG

genomics↗

bioRxiv2022

A subset of gut leukocytes have telomerase-dependent 'hyper-long' telomeres and require telomerase for function in zebrafish

Telomerase, the enzyme capable of elongating telomeres, is usually restricted in human somatic cells, which contributes to progressive telomere shortening with cell-division and ageing. Using the zebrafish model, we show that subsets gut immune cells have telomerase-dependent "hyper-long" telomeres, which we identified as being predominantly macrophages and dendritics (mpeg1.1+ and cd45+mhcII+). Notably, mpeg+ macrophages have much longer telomeres in the gut than in their haematopoietic tissue of origin, suggesting that there is a gut-specific modulation of telomerase in these cells. Moreover, we show that a subset of gut mpeg+ cells express telomerase (tert) in young WT zebrafish, but that the relative proportion of these cells decreases with ageing. Importantly, this is accompanied by telomere shortening and DNA damage responses with ageing and a telomerase-dependent decrease in expression of autophagy and immune activation markers. Finally, these telomerase-dependent molecular alterations are accompanied by impaired phagocytosis of E.coli and increased gut permeability in vivo. Together, our data show that limiting levels of telomerase lead to changes in gut immunity and gut permeability, which, together, are likely contributors to local and systemic tissue degeneration and increased susceptibility to infection with ageing. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/478480v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@141a6caorg.highwire.dtl.DTLVardef@12d24baorg.highwire.dtl.DTLVardef@c64267org.highwire.dtl.DTLVardef@319449_HPS_FORMAT_FIGEXP M_FIG C_FIG Our data show that limiting levels of telomerase contribute to alterations in gut immunity, namely increased apoptosis, decreased autophagy and immune activation of mpeg+ macrophages in the gut. This is accompanied by a decreased ability to clear pathogens and increased gut permeability. Together, these are likely contributors to local and systemic tissue degeneration and susceptibility to infection with ageing.

cell biology↗

bioRxiv2020

Age-related degeneration leads to gliosis but not regeneration in the zebrafish retina

Ageing is a significant risk factor for degeneration of the retina. Harnessing the regenerative potential of Muller glia cells (MG) in the retina offers great promise for the treatment of blinding conditions. Yet, the impact of ageing on MG regenerative capacity has not yet been considered. Here we show that the zebrafish retina undergoes telomerase-independent age-related neurodegeneration. Yet, this progressive neuronal loss in the ageing retina is insufficient to stimulate the MG regenerative response. Instead, age-related neurodegeneration leads to MG gliosis and loss of vision, similarly to humans. Nevertheless, gliotic MG cells retain Yap expression and the ability to regenerate neurons after acute light damage. Therefore, we identify key differences in the MG response to acute versus chronic damage in the zebrafish retina and show that aged gliotic MG can be stimulated to repair damaged neurons in old age. SUMMARY O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/174821v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1a184daorg.highwire.dtl.DTLVardef@1193750org.highwire.dtl.DTLVardef@7e65c0org.highwire.dtl.DTLVardef@4a2fe3_HPS_FORMAT_FIGEXP M_FIG C_FIG Our data suggest there are key differences between mechanisms driving regeneration in response to acute damage versus age-related chronic damage. It may be that either the number of cells dying in natural ageing is not enough to stimulate MG to proliferate, or the low number of microglia and respective signals released are not sufficient to trigger MG proliferation. Importantly, we show that gliotic MG cells can be stimulated to repair damaged neurons in old zebrafish retina.

neuroscience↗