Biology subjects

Gegg, M.

Publications and source records attributed to Gegg, M..

4 recordsLinked to original sources

bioRxiv2026

Elevated cholesterol in APOE4 astrocytes drives mitochondrial cristae collapse and ATP synthase dysfunction

Cholesterol imbalance is a hallmark of major human diseases, including atherosclerosis and Alzheimers disease, both of which are also associated with mitochondrial dysfunction, yet the mechanistic links between cholesterol and mitochondria remain poorly understood. Here we show that elevated intracellular cholesterol in murine astrocytes expressing the Alzheimers disease risk variant APOE4 disrupts the inner mitochondrial membrane, manifesting as sparse, truncated cristae alongside an excess of cristae junction complexes. These structural abnormalities are accompanied by loss of respiratory chain complexes I and IV, and reduced respiration; nevertheless, low proton leak and reverse ATP synthase activity combine to generate an elevated mitochondrial membrane potential. Strikingly, APOE4 astrocytes are hypersensitive to the ATP synthase inhibitor oligomycin, demonstrating a profound dysfunction of the enzyme, and cholesterol sequestration with methyl-{beta}-cyclodextrin abrogates this toxicity, establishing elevated cholesterol as its proximate cause. Another method of targeting ATP synthase, epicatechin, which prevents the enzyme operating in reverse, attenuated both cholesterol- and respiratory chain inhibitor-induced cell death. Reciprocally, reducing intracellular cholesterol via nutrient restriction restored cristae architecture and partially rescued respiratory chain complex abundance. These findings identify mitochondrial cholesterol as a critical determinant of cristae architecture and ATP synthase function and suggest that cholesterol-driven mitochondrial dysfunction may be a unifying feature of cholesterol-related disorders from neurodegeneration to atherosclerosis. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/742391v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@2e80a1org.highwire.dtl.DTLVardef@fecd32org.highwire.dtl.DTLVardef@51ba3corg.highwire.dtl.DTLVardef@199f3c6_HPS_FORMAT_FIGEXP M_FIG Elevated intracellular cholesterol in APOE4 astrocytes disrupts the inner mitochondrial membrane and ATP synthase, resulting in sparse cristae, increased ATP hydrolysis and heightened oligomycin sensitivity. The vulnerability to oligomycin is abrogated by cholesterol sequestration with cyclodextrin, indicating causality. These findings position cholesterol as a key determinant of the cristae landscape and ATP synthase function, highlighting the importance of the emerging field of mitochondrial-cholesterol crosstalk. C_FIG

cell biology↗

bioRxiv2024

Influence of the Glymphatic System on α-Synuclein Propagation: Role of Aquaporin-4 and the Dystrophin-Associated Protein Complex

Propagation and aggregation of prion proteins, such as tau and -synuclein (Syn), are key pathological features of neurodegenerative diseases. Extracellular clearance pathways, such as the glymphatic system, may play a crucial role in the removal of these toxic proteins from the brain. Primarily active during sleep, this system relies on aquaporin-4 (AQP4) water channel expression and polarisation to astrocytic endfeet, facilitating interstitial solute clearance. Glymphatic dysfunction has recently been implicated in Parkinsons disease, however the precise mechanisms underlying the pathogenic effect of this dysfunction remain unclear. This includes how impaired glymphatic function influences Syn propagation dynamics, and the role of propagating Syn itself on glymphatic function. In this study, we used a mouse model of Syn propagation to elucidate the impact of Syn aggregation on glymphatic function, by measuring CSF-ISF exchange and assessing AQP4 and associated endfoot complex proteins in the brain over time and across different regions. Our results show that direct injection of Syn pre-formed fibrils leads to reduced expression of the AQP4 endfoot complex, but propagation of endogenous Syn induces an enhancement of glymphatic function suggesting compensatory upregulation in response to increasing endogenous Syn load. To determine the influence of glymphatic dysfunction on Syn propagation dynamics, we then employed a pharmacological approach to inhibit glymphatic function in this model. Acute glymphatic inhibition significantly reduced brain to CSF Syn clearance, and chronic treatment exacerbated Syn pathology, neurodegeneration, and motor behavioural deficits in mice. Together our findings show that Syn clearance and propagation are modulated by glymphatic function and suggest that AQP4 complex dysregulation may contribute to glymphatic impairment associated with Parkinsons diseases. Summary for the non-scientific communityThe glymphatic system clears brain waste during sleep. Lopes et al. show that -synuclein, a protein linked to Parkinsons, is cleared by this system. Using a mouse model of the disease, they suggest that aquaporin-4 water channels may impair glymphatic function, contributing to -synuclein buildup in patients brains.

neuroscience↗

bioRxiv2024

Energy scarcity and impaired mitochondrial translation induce perinuclear stress granule clustering

Many proteins linked to amyotrophic lateral sclerosis and fronto-temporal dementia (ALS-FTD) change their cellular location and coalesce in cytoplasmic inclusion bodies in the disease state; yet the factors that govern protein relocation and organization remain unclear. Here, we show that inhibition of glycolysis and mitochondrial protein synthesis causes many proteins involved in ALS-FTD to change location, and form a novel structure comprising a ring of stress granules encircling the aggresome, a focal microtubule-based structure beside the nucleus. A perinuclear ring of stress granules also forms in activated microglia of mice exposed to the glycolytic inhibitor, 2-Deoxy-D-glucose. We propose that the new arrangement increases the risk of the stress granules merging and converting from the liquid phase to the insoluble inclusion characteristic of ALS-FTD. Thus, our findings suggest that that compromised nutrient and energy metabolism can precipitate a molecular cascade that ultimately leads to the pathological hallmark of ALS-FTD the perinuclear inclusion body. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/578399v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@b32d48org.highwire.dtl.DTLVardef@161f848org.highwire.dtl.DTLVardef@f35c66org.highwire.dtl.DTLVardef@1375508_HPS_FORMAT_FIGEXP M_FIG C_FIG Inhibition of glycolysis and mitochondrial protein synthesis induces translocation of a swathe of ALS-FTD related proteins in primary human fibroblasts. The relocated proteins form concentric cytoplasmic rings (CCR) comprising stress granules, the Golgi and the aggresome, beside the nucleus. A perinuclear ring of stress granules forms in the mouse brain following intermittent nutrient restriction, with the glucose analog 2DG. The CCR is potentially a key intermediate step in the formation of pathological inclusions and so perturbed nutrient and energy metabolism encompassing impaired mitochondrial translation could precipitate the ALS-FTD disease cascade.

cell biology↗

bioRxiv2019

Loss of acid sphingomyelinase ameliorates disease progression in a vertebrate model of Glucocerebrosidase deficiency

The additive effect of genetic risk variants on overall disease risk is a plausible but frequently unproven hypothesis. To test this hypothesis, we assessed the biological effect of combined glucocerebrosidase (GCase) and acid sphingomyelinase (ASM) deficiency. Variants in both glucocerebrosidase1 (GBA1) and sphingomyelinase (SMPD1) are genetic risk factors for Parkinsons disease. Unexpectedly, ASM deficiency resulted in normalized behaviour and prolonged survival in gba1-/-;smpd1-/- double-mutant zebrafish compared to gba1-/-. RNAseq-based pathway analysis confirmed a profound rescue of neuronal function and intracellular homeostasis. We identified complete reciprocal rescue of mitochondrial respiratory chain function and abolished lipid membrane oxidation in gba1-/-;smpd1-/- compared to gba1-/- or smpd1-/- as the underlying rescue mechanism. Complementing in vitro experiments demonstrated an unexpected reduction of -synuclein levels in human cell lines with combined GCase and ASM deficiency. Our study highlights the importance of functional validation for any putative interactions between genetic risk factors and their overall effect on disease-relevant mechanisms rather than readily assuming an additive effect. SummaryThe additive effect of genetic risk variants on disease risk is a popular but typically unproven hypothesis. We investigated this hypothesis mechanistically for Parkinsons disease risk factors and provide evidence of an unexpected rescue effect on neuronal function and survival.

genetics↗