Biology subjects

Brownlees, J.

Publications and source records attributed to Brownlees, J..

3 recordsLinked to original sources

bioRxiv2025

MitoTracker transfers from astrocytes to neurons independently of mitochondria

The neuroprotective transfer of mitochondria from astrocytes to neurons has been primarily investigated by labelling astrocytic mitochondria with the dye MitoTracker. Here we report that MitoTracker transfers to neurons from both astrocytes and astrocyte-conditioned media, independently of mitochondrial transfer. Our observations should prompt an essential re-evaluation of the literature concerning astrocyte-neuron mitochondrial transfer and in other systems in which contact-independent transfer has been observed using mitochondrial dyes.

neuroscience↗

bioRxiv2023

Disrupting the interaction between AMBRA1 and DLC1 is a promising therapeutic strategy for neurodegeneration that prevents apoptosis while enhancing autophagy and mitophagy

Activating molecule in Beclin1-regulated autophagy (AMBRA1) has critical roles in autophagy, mitophagy, cell cycle regulation, neurogenesis and apoptosis. Dysregulation of these processes are hallmarks of various neurodegenerative diseases and therefore AMBRA1 represents a potential therapeutic target. The flexibility of its intrinsically disordered regions allows AMBRA1 to undergo conformational changes and thus perform its function as an adaptor protein for various different complexes. Understanding the relevance of these multiple protein-protein interactions will allow us to gain information about which to target pharmacologically. To compare potential AMBRA1 activation strategies we have designed and validated several mutant constructs (ACTA, TAT, WD40 and S1014) in addition to characterising their effects on proliferation, apoptosis, autophagy and mitophagy in SHSY5Y cells. AMBRA1TAT, which is a mutant form of AMBRA1 that cant interact with dynein light chain (DLC)1 at the microtubules, produced the most promising results. Indeed, overexpression of this mutant protected cells against apoptosis and induced autophagy and mitophagy in SHSY5Y cells in addition to enhancing the switch from quiescence to proliferation in mouse neural stem cells. Future studies should focus on designing compounds that inhibit the protein-protein interaction between AMBRA1 and DLC1 and thus have potential to be used as a drug strategy to treat neurodegeneration.

cell biology↗

bioRxiv2020

Inhibition of IL34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in chronic neurodegeneration

The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimers disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cellular types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF1 and interleukin 34 (IL-34). Recently, it has been reported that microglia development and maintenance depend on IL-34 signalling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in neurodegenerative diseases, using the ME7 model of prion disease. Selective inhibition of IL-34 showed no effects on peripheral macrophages populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34 and that this ligand plays an important role in the modulation of microglia population during neurodegeneration. Overall, our results suggest that control of microglial response through IL-34 blockade could be a potential therapeutic approach in neurodegenerative diseases.

neuroscience↗