Biology subjects

Henstridge, C.

Publications and source records attributed to Henstridge, C..

3 recordsLinked to original sources

bioRxiv2021

Targeting tau mitigates mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis

Understanding the mechanisms underlying amyotrophic lateral sclerosis (ALS) is crucial for the development of new therapies. Recent evidence suggest that tau may be involved in ALS pathogenesis. Here, we demonstrated that hyperphosphorylated tau (pTau-S396) is mis-localized to synapses in human post-mortem motor cortex (mCTX) across ALS subtypes. Treatment with ALS synaptoneurosomes (SNs) derived from post-mortem mCTX, enriched in pTau-S396, increased oxidative stress, induced mitochondrial fragmentation, and altered mitochondrial connectivity in vitro. Furthermore, our findings revealed that pTau-S396 interacts with the pro-fission dynamin-related protein (DRP1), and similar to pTau-S396, DRP1 accumulated in ALS SNs across ALS subtypes. Lastly, reducing tau with a specific bifunctional degrader, QC-01-175, prevented ALS SNs-induced mitochondrial fragmentation and oxidative stress in vitro. Collectively, our findings suggest that increases in pTau-S396 may lead to mitochondrial fragmentation and oxidative stress in ALS and decreasing tau may provide a novel strategy to mitigate mitochondrial dysfunction in ALS. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/436505v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1d805baorg.highwire.dtl.DTLVardef@1601f49org.highwire.dtl.DTLVardef@1a62abforg.highwire.dtl.DTLVardef@40699f_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIpTau-S396 mis-localizes to synapses in ALS. C_LIO_LIALS synaptoneurosomes (SNs), enriched in pTau-S396, increase oxidative stress and induce mitochondrial fragmentation in vitro. C_LIO_LIpTau-S396 interacts with the pro-fission GTPase DRP1 in ALS. C_LIO_LIReducing tau with a specific degrader, QC-01-175, mitigates ALS SNs-induced mitochondrial fragmentation and increases in oxidative stress in vitro. C_LI

neuroscience↗

bioRxiv2020

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in ALS-FTD

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative diseases that are increasingly understood to have long prodromal periods. Investigation of these early stages promises to yield valuable biomarkers of disease and will be key to understanding mechanisms underlying the genesis of ALS-FTD. Here, we use in vivo magnetic resonance imaging (MRI), histology and computed tomography to identify structural and cellular readouts of early stage disease in the TDP-43Q331K knock-in mouse model of ALS-FTD. Adult mutant mice demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of ALS-FTD. Subcortical, cerebellar and brain stem regions were also affected in line with observations in presymptomatic carriers of mutations in C9orf72, the commonest genetic cause of both ALS and FTD. Volume loss, as measured by MRI, was also observed in the dentate gyrus (DG) of the hippocampus, along with ventricular enlargement. Guided by these imaging findings, detailed post-mortem brain tissue analysis revealed reduced parvalbumin-positive (PV+) interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia were in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the DG, indicative of impaired adult neurogenesis, while a paucity of PV+ interneurons in juvenile mutant mice (P14) suggests that TDP-43Q331K disrupts neurodevelopment. Computerised tomography imaging also showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem prefrontal cortices confirmed a paucity of PV+ interneurons in the prefrontal cortex in cases with both sporadic ALS and ALS linked to C9orf72 mutations. This study suggests an important role for PV+ interneurons in regional brain vulnerability associated with ALS-FTD, and identifies novel MRI and histological biomarkers that will be of value in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice.

neuroscience↗

bioRxiv2019

Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype

Degeneration of synapses in Alzheimers disease (AD) strongly correlates with cognitive decline, and synaptic pathology contributes to disease pathophysiology. We recently discovered that the strongest genetic risk factor for sporadic AD, apolipoprotein E epsilon 4 (APOE4), exacerbates synapse loss and synaptic accumulation of oligomeric amyloid beta in human AD brain. To begin to understand the molecular cascades involved in synapse loss in AD and how this is mediated by APOE, and to generate a resource of knowledge of changes in the synaptic proteome in AD, we conducted a proteomic screen and systematic in-silico analysis of synaptoneurosome preparations from temporal and occipital cortices of human AD and control subjects with known APOE gene status. Our analysis identified over 5,500 proteins in human synaptoneurosomes and highlighted disease, brain region, and APOE-associated changes in multiple molecular pathways including a decreased abundance in AD of proteins important for synaptic and mitochondrial function and an increased abundance of proteins involved in neuroimmune interactions and intracellular signaling.\n\nHighlightsO_LIProteomic analysis of synapses isolated from Alzheimers disease and control subject brains identifies over 5,500 proteins in human synapses.\nC_LIO_LIIn silico analysis reveals region-specific decreases in proteins involved in synaptic and mitochondrial function and increases in proteins involved in neuroimmune signaling and intracellular signaling in AD.\nC_LIO_LIThe apolipoprotein E4 risk gene is associated with exacerbated changes in synaptic proteins in AD.\nC_LI

neuroscience↗