Huntingtin inclusion bodies have distinct immunophenotypes and ubiquitination profiles in the Huntington's disease human cerebral cortex.

Huntington's disease (HD) is a hereditary neurodegenerative condition caused by a CAG repeat expansion mutation in the gene encoding the huntingtin (HTT) protein. The accumulation of HTT inclusion bodies is a pathological hallmark of HD and a common target for therapeutic strategies. However, the limited efficacy of treatments targeting the HTT protein highlights the need for a better understanding of the role of HTT inclusion bodies in HD pathogenesis.

Mutant huntingtin induces neuronal apoptosis via derepressing the non-canonical poly(A) polymerase PAPD5.

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).

MRI-T2 Relaxometry is Increased in Mild Traumatic Brain Injury: Indications of Acute Brain Abnormalities After Injury.

Mild traumatic brain injury (mTBI) is a common condition, particularly pervasive in contact sports environments. A range of symptoms can accompany this type of injury and negatively impact people's lives. As mTBI diagnosis and recovery largely rely on subjective reports, more objective injury markers are needed.

Mild traumatic brain injury increases cortical iron: evidence from individual susceptibility mapping.

Quantitative susceptibility mapping has been applied to map brain iron distribution after mild traumatic brain injury to understand properties of neural tissue which may be related to cellular dyshomeostasis. However, this is a heterogeneous injury associated with microstructural brain changes, and 'traditional' group-wise statistical approaches may lead to a loss of clinically relevant information, as subtle alterations at the individual level can be obscured by averages and confounded by within-group variability. More precise and individualized approaches are needed to characterize mild traumatic brain injury better and elucidate potential cellular mechanisms to improve intervention and rehabilitation.

Characterizing positive and negative quantitative susceptibility values in the cortex following mild traumatic brain injury: a depth- and curvature-based study.

Evidence has linked head trauma to increased risk factors for neuropathology, including mechanical deformation of the sulcal fundus and, later, perivascular accumulation of hyperphosphorylated tau adjacent to these spaces related to chronic traumatic encephalopathy. However, little is known about microstructural abnormalities and cellular dyshomeostasis in acute mild traumatic brain injury in humans, particularly in the cortex. To address this gap, we designed the first architectonically motivated quantitative susceptibility mapping study to assess regional patterns of net positive (iron-related) and net negative (myelin-, calcium-, and protein-related) magnetic susceptibility across 34 cortical regions of interest following mild traumatic brain injury.

Neuronal TDP-43 aggregation drives changes in microglial morphology prior to immunophenotype in amyotrophic lateral sclerosis.

Microglia are the innate immune cells of the brain with the capacity to react to damage or disease. Microglial reactions can be characterised in post-mortem tissues by assessing their pattern of protein expression, or immunophenotypes, and cell morphologies. We recently demonstrated that microglia have a phagocytic immunophenotype in early-stage ALS but transition to a dysfunctional immunophenotype by end stage, and that these states are driven by TAR DNA-binding protein 43 (TDP-43) aggregation in the human brain.

Perivascular glial reactivity is a feature of phosphorylated tau lesions in chronic traumatic encephalopathy.

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.

Refining α-synuclein seed amplification assays to distinguish Parkinson's disease from multiple system atrophy.

Background: Parkinson's disease (PD) and multiple system atrophy (MSA) are two distinct α-synucleinopathies traditionally differentiated through clinical symptoms. Early diagnosis of MSA is problematic, and seed amplification assays (SAAs), such as real-time quaking-induced conversion (RT-QuIC), offer the potential to distinguish these diseases through their underlying α-synuclein (α-Syn) pathology and proteoforms. Currently, SAAs provide a binary result, signifying either the presence or absence of α-Syn seeds.

Elucidating cortical neurovascular involvement in Huntington's disease using human brain tissue microarrays.

Although the genetic basis of Huntington's disease (HD) has been determined, the underlying pathophysiological mechanisms contributing to neurodegeneration remain largely unknown. In recent years, increasing evidence has posited vascular dysfunction as a significant early event in disease pathogenesis; however, these processes remain to be fully elucidated. High-content immunohistochemical screening studies were conducted on HD middle temporal gyrus (MTG) human brain tissue microarrays (TMAs) to investigate various components of the vascular system, including endothelial cells (UEA-1), pericytes (PDGFRβ), vascular smooth muscle cells (αSMA), extracellular matrix components (ECM; collagen IV and fibronectin), and leakage markers (haemoglobin and fibrinogen).

Aberrant splicing in Huntington's disease accompanies disrupted TDP-43 activity and altered m6A RNA modification.

Huntington's disease (HD) is caused by a CAG repeat expansion in the HTT gene, leading to altered gene expression. However, the mechanisms leading to disrupted RNA processing in HD remain unclear. Here we identify TDP-43 and the N6-methyladenosine (m6A) writer protein METTL3 to be upstream regulators of exon skipping in multiple HD systems.

N-terminus α-synuclein detection reveals new and more diverse aggregate morphologies in multiple system atrophy and Parkinson's disease.

Background: Parkinson's disease (PD) and multiple system atrophy (MSA) are classified as α-synucleinopathies and are primarily differentiated by their clinical phenotypes. Delineating these diseases based on their specific α-synuclein (α-Syn) proteoform pathologies is crucial for accurate antemortem biomarker diagnosis. Newly identified α-Syn pathologies in PD raise questions about whether MSA exhibits a similar diversity.

Upregulated excitatory amino acid transporter 1 (EAAT1) expression in the human medial temporal lobe in Alzheimer's disease.

Alzheimer's disease (AD) is a growing health problem worldwide, particularly in the developed world due to an ageing population. Glutamate excitotoxicity plays a major role in the pathophysiology of AD, and glutamate re-uptake is controlled by excitatory amino acid transporters (EAATs). The EAAT2 isoform is the predominant transporter involved in glutamate reuptake, therefore EAAT1 has not been the focus of AD research.

Enhanced detection of distinct honeycomb-structured neuronal SMARCC2 cytobodies in Parkinson's Disease via Cyclic Heat-Induced Epitope Retrieval (CHIER).

Antigen retrieval is crucial for immunohistochemistry, particularly in formalin-fixed paraffin-embedded brain tissue, where fixation causes extensive crosslinking that masks epitopes. Heat Induced Epitope Retrieval (HIER) reverses these crosslinks, improving access to nuclear and aggregated proteins. We introduce Cyclic Heat-Induced Epitope Retrieval (CHIER), an advanced technique that builds on HIER by incorporating repeated cycles of heating and cooling.

Astrocytic proteins involved in regulation of the extracellular environment are increased in the Alzheimer's disease middle temporal gyrus.

Alzheimer's disease (AD) has complex pathophysiology involving numerous cell types and brain processes. Astrocyte involvement in AD is gaining increased attention, however a complete characterisation of astrocytic changes in the AD human brain is warranted. Astrocytes perform important homeostatic functions including regulation of the extracellular microenvironment, critical for the health of all brain cells.

Individual-level analysis of MRI T2 relaxometry in mild traumatic brain injury: Possible indications of brain inflammation.

Mild traumatic brain injury (mTBI), often called concussion, is a prevalent condition that can have significant implications for people's health, functioning and well-being. Current clinical practice relies on self-reported symptoms to guide decision-making regarding return to sport, employment, and education. Unfortunately, reliance on subjective evaluations may fail to accurately reflect the resolution of neuropathology, exposing individuals with mTBI to an increased risk of further head trauma.

Huntingtin is an RNA binding protein and participates in -mediated paraspeckles.

Huntingtin protein, mutated in Huntington's disease, is implicated in nucleic acid-mediated processes, yet the evidence for direct huntingtin-nucleic acid interaction is limited. Here, we show wild-type and mutant huntingtin copurify with nucleic acids, primarily RNA, and interact directly with G-rich RNAs in in vitro assays. Huntingtin RNA-immunoprecipitation sequencing from patient-derived fibroblasts and neuronal progenitor cells expressing wild-type and mutant huntingtin revealed long noncoding RNA as a significantly enriched transcript.

Characterization of neurofibrillary tangle immunophenotype signatures to classify tangle maturity in Alzheimer's disease.

Introduction: Tau aggregation into neurofibrillary tangles in Alzheimer's disease (AD) is a dynamic process involving changes in tau phosphorylation, isoform composition, and morphology. To facilitate studies of tangle maturity, we developed an image analysis pipeline to study antibody labeling signatures that can distinguish tangle maturity levels in AD brain tissue.

Methods: Using fluorescent immunohistochemistry, we co-labeled AD brain tissue with four antibodies that bind different tau epitopes.

Microglial proliferation and astrocytic protein alterations in the human Huntington's disease cortex.

Huntington's disease (HD) is a neurodegenerative disorder that severely affects the basal ganglia and regions of the cerebral cortex. While astrocytosis and microgliosis both contribute to basal ganglia pathology, the contribution of gliosis and potential factors driving glial activity in the human HD cerebral cortex is less understood. Our study aims to identify nuanced indicators of gliosis in HD which is challenging to identify in the severely degenerated basal ganglia, by investigating the middle temporal gyrus (MTG), a cortical region previously documented to demonstrate milder neuronal loss.

Ultrastructural localization of Porphyromonas gingivalis gingipains in the substantia nigra of Parkinson's disease brains.

Gingipains are protease virulence factors produced by Porphyromonas gingivalis, a Gram-negative bacterium best known for its role in chronic periodontitis. Gingipains were recently identified in the middle temporal gyrus of postmortem Alzheimer's disease (AD) brains, where gingipain load correlated with AD diagnosis and tau and ubiquitin pathology. Since AD and Parkinson's disease (PD) share some overlapping pathologic features, including nigral pathology and Lewy bodies, the current study explored whether gingipains are present in the substantia nigra pars compacta of PD brains.

Pharmacology of PACAP and VIP receptors in the spinal cord highlights the importance of the PAC receptor.

Background And Purpose: The spinal cord is a key structure involved in the transmission and modulation of pain. Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP), are expressed in the spinal cord. These peptides activate G protein-coupled receptors (PAC, VPAC and VPAC) that could provide targets for the development of novel pain treatments.

Alzheimer's Disease-associated Region-specific Decrease of Vesicular Glutamate Transporter Immunoreactivity inthe Medial Temporal Lobe and Superior Temporal Gyrus.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are very limited treatment options. Dysfunction of the excitatory neurotransmitter system is thought to play a major role in the pathogenesis of this condition. Vesicular glutamate transporters (VGLUTs) are key to controlling the quantal release of glutamate.

Distribution of ubiquilin 2 and TDP-43 aggregates throughout the CNS in UBQLN2 p.T487I-linked amyotrophic lateral sclerosis and frontotemporal dementia.

Mutations in the UBQLN2 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of such UBQLN2-linked cases of ALS/FTD is characterised by aggregates of the ubiquilin 2 protein in addition to aggregates of the transactive response DNA-binding protein of 43 kDa (TDP-43). ALS and FTD without UBQLN2 mutations are also characterised by TDP-43 aggregates, that may or may not colocalise with wildtype ubiquilin 2.