Biology subjects

Brenton, J. W.

Publications and source records attributed to Brenton, J. W..

6 recordsLinked to original sources

bioRxiv2025

Alternate Splicing Directs PMCA2 to Lysosomes and is Linked to Neurodegeneration

Plasma membrane calcium ATPases (PMCAs) are believed to function exclusively at the plasma membrane where they expel calcium from the cytosol. We have unexpectedly identified a splice variant-dependent localisation of the PMCA isoform PMCA2 to the lysosome, where it forms an evolutionarily conserved complex with NPC1, the lysosomal membrane protein defective in the rare lysosomal storage disease Niemann-Pick disease type C (NPC). This interaction is required for lysosomal Ca2+ homeostasis and implicates PMCA2 as a mediator of Ca2+ uptake into lysosomes. Disruption of the NPC1-PMCA2 complex contributes to the pathophysiology of both Niemann-Pick disease type C and Parkinsons disease, revealing an unrecognised intracellular function for PMCA2 and a shared mechanism linking lysosomal Ca2+ and lipid regulation in neurodegeneration.

cell biology↗

bioRxiv2025

TDP-43 loss of function drives aberrant splicing in Parkinson's disease

Introductory paragraphWhile mRNA splicing dysregulation is a well-established contributor to neurodegeneration in disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), its role in Parkinsons disease (PD) remains underexplored. Here, we analyse transcriptomic data from >500 post-mortem human brain samples from individuals with and without PD to show that splicing alterations are frequently detected. Differentially spliced genes were significantly more enriched for those causally-implicated in both PD and ALS than genes that were differentially expressed. Furthermore, we observed a strong association between these splicing alterations and dysfunction of the RNA-binding protein (RBP), TAR DNA-binding protein 43 (TDP-43). Strikingly, genes and exon junctions affected by TDP-43 knockdown overlapped significantly with those dysregulated across brain regions in PD. In brains from individuals with the LRRK2 c.6055G>A (p.G2019S) mutation, the most common genetic cause of PD, we also observed significant enrichment of TDP-43-dependent splicing changes. This finding was corroborated in human pluripotent stem cell-derived midbrain dopaminergic neurons and a LRRK2 p.G2019S knock-in mouse model, where reduced nuclear TDP-43 levels evidenced the well-recognised loss-of-function mechanism contributing to splicing dysregulation. By leveraging our RNA-based analyses we predicted TDP-43-dependent novel peptide sequences and validated their existence within human LRRK2 mutation mDNs, while also demonstrating an overall loss of protein and mRNA expression in mis-spliced genes. Collectively, our findings reveal that PD is marked by extensive splicing dysregulation dependent on TDP-43, making TDP-43 a promising new therapeutic target in PD.

neuroscience↗

bioRxiv2025

Microglial activation and alpha-synuclein oligomers drive the early inflammatory phase of Parkinson's disease

Parkinsons disease (PD) is characterised by insoluble -synuclein (Syn) aggregates in Lewy bodies (LBs) within the substantia nigra, with cortical pathology appearing as the disease progresses. Late-stage LB deposition, cellular stress, and neuronal loss obscure disease-driving events, we therefore performed multi-regional transcriptomic and aggregate profiling in early-midstage PD brains (Braak 3-4), where cortical regions are pathologically unaffected. We report neuroimmune activation as an early PD feature, characterised by the expansion of a high-SNCA-expressing microglial state. This robust immune signature occurs prior to LB formation, but is associated with oligomeric Syn within cortical microglia. In hiPSC-derived microglia, both endogenous Syn oligomerisation, and exogenous oligomer uptake, trigger transcriptional reprogramming, characterised by interferon-driven inflammation, antigen presentation, and mitochondrial suppression, closely mirroring the early PD brain. These findings describe mechanisms by which Syn oligomerisation potently initiates early neuroinflammation, highlighting a critical interplay between proteinopathy and immune activation at the earliest stages of disease.

neuroscience↗

bioRxiv2025

17q21.31 locus regulates Parkinson's disease relevant pathways through KANSL1 activity

An inversion polymorphism at the 17q21.31 locus defines the H1 and H2 haplotypes, with the former linked to multiple neurodegenerative disorders, including an increased risk of Parkinsons disease (PD). Although the high linkage disequilibrium at this locus has made it difficult to decipher which gene(s) drive the PD association, there is increasing evidence to support the role of KANSL1 as a risk gene. KANSL1 has been shown to regulate the expression of some PD-associated genes and pathways, likely as part of the histone acetylating non-specific lethal (NSL) complex. Here for the first time, we studied the global effects of 17q21.31 haplotype variation using bulk and single-nuclear RNA-sequencing data from control and PD patient brain. We first analysed differential gene expression across haplotype groups, and then assessed the contribution of KANSL1 by comparing with the results of an siRNA knockdown in neuronal and glial human cell lines. We demonstrated that the PD risk-associated H1 haplotype downregulates autophagy, lysosomal and mitochondrial processes, all of which have already been implicated in PD aetiology. Furthermore, these effects were apparent in both neuronal and glial cell types, and in the case of the latter, appear to be associated with the modulation of innate and adaptive immune responses. Thus, we identify important links between NSL complex activity and PD pathophysiology that can be leveraged for novel therapeutic interventions.

neuroscience↗

bioRxiv2025

Molecular and cellular signatures differentiate Parkinson's disease from Parkinson's disease with dementia

Parkinsons disease (PD) affects millions of people worldwide, and up to 40% of these patients develop dementia, profoundly affecting their quality of life. Whether Parkinsons disease dementia (PDD) simply represents a late stage of PD or constitutes a distinct neurodegenerative process remains unresolved. To clarify this, we generated the largest single nuclear transcriptomic atlas of PD and PDD to date--almost one million nuclei derived from the anterior cingulate cortex and inferior parietal lobule of 64 post-mortem donors. By integrating these data with long-read RNA-seq, we found that the cellular compositions, biological pathways, and molecular profiles diverge substantially between PD and PDD, with limited overlap in differentially expressed genes and pathways. While PD was characterised by widespread upregulation of gene expression programs and robust regional signatures, PDD showed extensive pathway downregulation, loss of cortical regional identity, and significant shifts in transcript usage, including alterations in APP isoforms that may influence pathological amyloid beta accumulation. These findings reveal that PD and PDD represent fundamentally distinct disease states, offering important insights for understanding their underlying mechanisms and will guide the development of targeted therapies and more effective clinical trials.

neuroscience↗

bioRxiv2023

Splicing accuracy varies across human introns, tissues and age

Alternative splicing impacts most multi-exonic human genes. Inaccuracies during this process may have an important role in ageing and disease. Here, we investigated mis-splicing using RNA-sequencing data from ~14K control samples and 42 human body sites, focusing on split reads partially mapping to known transcripts in annotation. We show that mis-splicing occurs at different rates across introns and tissues and that these splicing inaccuracies are primarily affected by the abundance of core components of the spliceosome assembly and its regulators. Using publicly available data on short-hairpin RNA-knockdowns of numerous spliceosomal components and related regulators, we found support for the importance of RNA-binding proteins in mis-splicing. We also demonstrated that age is positively correlated with mis-splicing, and it affects genes implicated in neurodegenerative diseases. This in-depth characterisation of mis-splicing can have important implications for our understanding of the role of splicing inaccuracies in human disease and the interpretation of long-read RNA-sequencing data.

genetics↗