Maurice A. Curtis

Parkinson’s disease (PD) is characterized by the build-up of α-synuclein (α-syn) in the brain, where it drives neurodegeneration. Importantly, aggregated α-syn also accumulates in the cerebrospinal fluid (CSF) of PD patients, and while increasingly used for diagnosis, its pathological role remains poorly understood. Here, we demonstrate that α-syn accumulation in central nervous system (CNS) border tissues promotes CNS clearance deficits, as observed in PD patients. We find that aggregated α-syn accumulates not only in the CSF but also in the dura mater of individuals with PD, and, using acute and chronic mouse models, show that α-syn deposition in these sites induces immune alterations in CNS borders and disrupts CNS clearance. Mechanistically, we reveal that α-syn at CNS borders elevates CSF TNF and demonstrate that both TNF and α-syn aggregates themselves impair lymphatic endothelial cell function. These findings demonstrate a pathological role for α-syn in the CNS border tissues and position meningeal immunity as a contributor to CNS clearance deficits in PD pathogenesis.

Post-mortem human brain tissue is an irreplaceable resource for advancing understanding of the brain and neurological disease. Brain banks that collect, preserve, and distribute this tissue underpin discoveries across neuropathology, genomics, and emerging molecular disciplines. Yet brain banking is a resource-intensive enterprise that faces distinct operational, cultural, and scientific challenges depending on the national context in which it operates. Here, we present the perspective of the Neurological Foundation Human Brain Bank (NFHuBB) — New Zealand’s sole post-mortem human brain bank, based at The University of Auckland. Operating as the only such facility in the country, the NFHuBB confronts a unique convergence of challenges: the logistical complexity of coordinating donation across a dispersed population, the scientific imperative to preserve tissue for molecular-era multi-omics technologies, and a multi-cultural population that needs culturally informed consent practices. We describe the growth of the bank’s donor registry and collection over 45 years with specific emphasis on donations in the last five calendar years (2021–2025), outline recent advances in tissue processing, including the development of formalin-fixed paraffin-embedded (FFPE) RNA preservation protocols and integration of whole-genome sequencing from un-fixed cerebellar tissue. Finally, we discuss the community engagement strategies that have supported increasing donation rates in New Zealand.

Desensitisation to insulin nearly doubles the risk of developing Alzheimer's disease (AD), a degenerative brain disorder and the leading cause of dementia. Impairment of the insulin signalling pathway is also apparent in AD brain tissue even in the absence of body‐wide insulin resistance. Activation of the insulin receptor (IR) in the brain increases neural resilience by promoting structural and synaptic plasticity, glucose metabolism, and resistance to apoptosis, thereby enhancing cognition and learning. Additionally, the splice variants of IR have differing downstream effects, and their ratio may play a role in insulin resistance. I n this work, the immunolabelling pattern and binding specificity of a range of IR beta subunit (IRβ) antibodies was studied in post‐mortem human brain tissue. Immunoreactivity in brain tissue was observed on almost all neurons and some astrocytes, but no other glia. Further, isoforms of IR transcripts both with and without exon 11 (IR‐B and IR‐A respectively) were identified within neurons and quantified in situ in the aged normal and AD entorhinal cortex (EC) and middle temporal gyrus (MTG) using RNAscope. Our results demonstrate the mRNA for both isoforms were abundant in similar quantities. However, IR‐B (Ex11 ⁺ ), the more efficient isoform, was predominant in the EC in AD, potentially reflecting a compensatory effect of brain insulin resistance. image

Amyotrophic lateral sclerosis (ALS) is a movement disorder lacking effective diagnostics and therapeutics, largely due to its clinical and etiological hete

MicroRNAs (miRNAs) are small non-coding RNAs that play crucial roles in post-transcriptional gene regulation. Poly(A) RNA polymerase D5 (PAPD5) catalyzes the addition of adenosine to the 3′ end of miRNAs. In this study, we demonstrate that the Yin Yang 1 protein, a transcriptional repressor of PAPD5, is recruited to both RNA foci and protein aggregates, resulting in an upregulation of PAPD5 expression in Huntington’s disease (HD). Additionally, we identify a subset of PAPD5-regulated miRNAs with increased adenylation and reduced expression in our disease model. We focus on miR-7-5p and find that its reduction causes the activation of the TAB2-mediated TAK1–MKK4–JNK pro-apoptotic pathway. This pathway is also activated in induced pluripotent stem cell-derived striatal neurons and post-mortem striatal tissues isolated from HD patients. In addition, we discover that a small molecule PAPD5 inhibitor, BCH001, can mitigate cell death and neurodegeneration in our disease models. This study highlights the importance of PAPD5-mediated miRNA dysfunction in HD pathogenesis and suggests a potential therapeutic direction for the disease.

Chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head injuries, is characterised by perivascular hyperphosphorylated tau (p-tau) accumulations within the depths of cortical sulci. Although the majority of CTE literature focuses on p-tau pathology, other pathological features such as glial reactivity, vascular damage, and axonal damage are relatively unexplored. In this study, we aimed to characterise these other pathological features, specifically in CTE p-tau lesion areas, to better understand the microenvironment surrounding the lesion. We utilised multiplex immunohistochemistry to investigate the distribution of 32 different markers of cytoarchitecture and pathology that are relevant to both traumatic brain injury and neurodegeneration. We qualitatively assessed the multiplex images and measured the percentage area of labelling for each marker in the lesion and non-lesion areas of CTE cases. We identified perivascular glial reactivity as a prominent feature of CTE p-tau lesions, largely driven by increases in astrocyte reactivity compared to non-lesion areas. Furthermore, we identified astrocytes labelled for both NAD(P)H quinone dehydrogenase 1 (NQO1) and L-ferritin, indicating that lesion-associated glial reactivity may be a compensatory response to iron-induced oxidative stress. Our findings demonstrate that perivascular inflammation is a consistent feature of the CTE pathognomonic lesion and may contribute to the pathogenesis of brain injury-related neurodegeneration.

Visualizing in 3D the histological microanatomy of the human olfactory projection from the olfactory mucosa in the nasal cavity to the olfactory bulbs in the cranial cavity necessitates a workflow for handling a great many sections. Here, we assembled a 3D reconstruction of a 7.45 cm³en-bloc specimen extracted from an embalmed human cadaver. A series of 10 µm coronal sections was stained with quadruple fluorescence histology and scanned in four channels. A trained anatomist manually segmented six structures of interest in a subset of the sections to generate the ground truth. Six convolutional neural networks were then trained for automatic segmentation of these structures in 1234 sections. A high-performance computing solution was engineered to register the sections based on the fluorescence signal and segmented structures. The resulting 3D visualization offers several novel didactic opportunities of interactive exploration and virtual manipulation. By extrapolating manual counts of OSNs in a subset of sections to the calculated volume of the envelope of the entire olfactory epithelium, we computed a total of ~2.7 million OSNs in the specimen. Such empirically derived information helps assess the extent to which the organizational principles of the human olfactory projection may differ from those in mice.