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1.
Neuropsychol Rehabil ; : 1-30, 2024 Aug 05.
Article in English | MEDLINE | ID: mdl-39102382

ABSTRACT

Although one of the most prevalent and impactful features of Huntington's disease (HD), little is known about the impact of apathy on HD caregivers, although there is evidence it affects perceptions of distress and burden. Given the importance of the caregivers, we aimed to explore the lived experience of people supporting someone with HD and associated apathy. Semi-structured interviews were conducted with 11 caregivers and analysed using reflective thematic analysis, informed by a phenomenological framework. Five overarching themes were produced: (1) What even is apathy? (2) It makes my life harder: the practical impact of apathy, (3) They haven't forgotten me, but they have forgotten that they ever loved me, (4) I'm grieving for someone who hasn't died yet, and (5) I need a safe space to say what I really feel without fear of judgement. Inter-woven between these themes were complex narratives about the unspoken nature of HD, the invisibility of caregivers who felt trapped and unheard, and the one-sided nature of loving someone with the disease. Findings are discussed in relation to theoretical frameworks of anticipatory grief and ambiguous loss, and situated within the wider literature on caregiving for people with a neurodegenerative condition.

2.
Alzheimers Dement (Amst) ; 16(3): e12625, 2024.
Article in English | MEDLINE | ID: mdl-39104403

ABSTRACT

Introduction: A subset of people with Parkinson's disease (PD) develop dementia faster than others. We aimed to profile PD cognitive subtypes at risk of dementia based on their rate of cognitive decline. Method: Latent class mixed models stratified subtypes in Parkinson's Progression Markers Initiative (PPMI) (N = 770) and ICICLE-PD (N = 212) datasets based on their decline in the Montreal Cognitive Assessment over at least 4 years. Baseline demographic and cognitive data at diagnosis were compared between subtypes to determine their clinical profile. Results: Four subtypes were identified: two with stable cognition, one with steady decline, and one with rapid decline. Performance on Judgement of Line Orientation, but not category fluency, was associated with a steady decline in the PPMI dataset, and deficits in category fluency, but not visuospatial function, were associated with a steady decline in the ICICLE-PD dataset. Discussion: People with PD susceptible to cognitive decline demonstrate unique clinical profiles at diagnosis, although this differed between cohorts. Highlights: Four cognitive subtypes were revealed in two Parkinson's disease samples.Unique profiles of cognitive impairment were related to cognitive decline.Judgement of Line Orientation/category fluency predictive of steady decline.Global deficits related to rapid cognitive decline and increased dementia risk.

3.
Bioessays ; : e2400118, 2024 Jul 26.
Article in English | MEDLINE | ID: mdl-39058892

ABSTRACT

Parkinson's disease (PD) is characterized by the loss of the dopaminergic nigrostriatal pathway which has led to the successful development of drug therapies that replace or stimulate this network pharmacologically. Although these drugs work well in the early stages of the disease, over time they produce side effects along with less consistent clinical benefits to the person with Parkinson's (PwP). As such there has been much interest in repairing this pathway using transplants of dopamine neurons. This work which began 50 years ago this September is still ongoing and has now moved to first in human trials using human pluripotent stem cell-derived dopaminergic neurons. The results of these trials are eagerly awaited although proof of principle data has already come from trials using human fetal midbrain dopamine cell transplants. This data has shown that developing dopamine cells when transplanted in the brain of a PwP can survive long term with clinical benefits lasting decades and with restoration of normal dopaminergic innervation in the grafted striatum. In this article, we discuss the history of this field and how this has now led us to the recent stem cell trials for PwP.

4.
NPJ Parkinsons Dis ; 10(1): 113, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38849413

ABSTRACT

There are 90 independent genome-wide significant genetic risk variants for Parkinson's disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out genome-wide survival studies for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We also identified a locus within the TBXAS1 gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near MORN1, ASNS, PDE5A, and XPO1. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, these may represent new candidates for disease modification in PD.

5.
Sci Adv ; 10(26): eadk1296, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38924406

ABSTRACT

Mutations in GBA1 cause Gaucher disease and are the most important genetic risk factor for Parkinson's disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, GBAP1. We show that >50% of short RNA-sequencing reads mapping to GBA1 also map to GBAP1. Thus, we used long-read RNA sequencing in the human brain, which allowed us to accurately quantify expression from both GBA1 and GBAP1. We discovered significant differences in expression compared to short-read data and identify currently unannotated transcripts of both GBA1 and GBAP1. These included protein-coding transcripts from both genes that were translated in human brain, but without the known lysosomal function-yet accounting for almost a third of transcription. Analyzing brain-specific cell types using long-read and single-nucleus RNA sequencing revealed region-specific variations in transcript expression. Overall, these findings suggest nonlysosomal roles for GBA1 and GBAP1 with implications for our understanding of the role of GBA1 in health and disease.


Subject(s)
Glucosylceramidase , Pseudogenes , Humans , Glucosylceramidase/genetics , Glucosylceramidase/metabolism , Pseudogenes/genetics , Brain/metabolism , Molecular Sequence Annotation , Parkinson Disease/genetics , Parkinson Disease/metabolism , Gaucher Disease/genetics , Sequence Analysis, RNA/methods
7.
Expert Opin Investig Drugs ; 33(5): 451-467, 2024 May.
Article in English | MEDLINE | ID: mdl-38758356

ABSTRACT

INTRODUCTION: Huntington's Disease (HD) is a genetic neurodegenerative disease for which there is currently no disease-modifying treatment. One of several underlying mechanisms proposed to be involved in HD pathogenesis is inflammation; there is now accumulating evidence that the immune system may play an integral role in disease pathology and progression. As such, modulation of the immune system could be a potential therapeutic target for HD. AREAS COVERED: To date, the number of trials targeting immune aspects of HD has been limited. However, targeting it, may have great advantages over other therapeutic areas, given that many drugs already exist that have actions in this system coupled to the fact that inflammation can be measured both peripherally and, to some extent, centrally using CSF and PET imaging. In this review, we look at evidence that the immune system and the newly emerging area of the microbiome are altered in HD patients, and then present and discuss clinical trials that have targeted different parts of the immune system. EXPERT OPINION: We then conclude by discussing how this field might develop going forward, focusing on the role of imaging and other biomarkers to monitor central immune activation and response to novel treatments in HD.


Subject(s)
Biomarkers , Huntington Disease , Inflammation , Huntington Disease/drug therapy , Huntington Disease/physiopathology , Huntington Disease/immunology , Humans , Animals , Inflammation/drug therapy , Inflammation/immunology , Biomarkers/metabolism , Molecular Targeted Therapy , Disease Progression , Drug Development , Immune System/drug effects , Microbiota
8.
Nature ; 2024 May 01.
Article in English | MEDLINE | ID: mdl-38693260

ABSTRACT

The human brain develops through a tightly organized cascade of patterning events, induced by transcription factor expression and changes in chromatin accessibility. Although gene expression across the developing brain has been described at single-cell resolution1, similar atlases of chromatin accessibility have been primarily focused on the forebrain2-4. Here we describe chromatin accessibility and paired gene expression across the entire developing human brain during the first trimester (6-13 weeks after conception). We defined 135 clusters and used multiomic measurements to link candidate cis-regulatory elements to gene expression. The number of accessible regions increased both with age and along neuronal differentiation. Using a convolutional neural network, we identified putative functional transcription factor-binding sites in enhancers characterizing neuronal subtypes. We applied this model to cis-regulatory elements linked to ESRRB to elucidate its activation mechanism in the Purkinje cell lineage. Finally, by linking disease-associated single nucleotide polymorphisms to cis-regulatory elements, we validated putative pathogenic mechanisms in several diseases and identified midbrain-derived GABAergic neurons as being the most vulnerable to major depressive disorder-related mutations. Our findings provide a more detailed view of key gene regulatory mechanisms underlying the emergence of brain cell types during the first trimester and a comprehensive reference for future studies related to human neurodevelopment.

9.
Chembiochem ; 25(11): e202400152, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38695673

ABSTRACT

Positron emission tomography imaging of misfolded proteins with high-affinity and selective radioligands has played a vital role in expanding our knowledge of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. The pathogenesis of Huntington's disease, a CAG trinucleotide repeat disorder, is similarly linked to the presence of protein fibrils formed from mutant huntingtin (mHTT) protein. Development of mHTT fibril-specific radioligands has been limited by the lack of structural knowledge around mHTT and a dearth of available hit compounds for medicinal chemistry refinement. Over the past decade, the CHDI Foundation, a non-for-profit scientific management organisation has orchestrated a large-scale screen of small molecules to identify high affinity ligands of mHTT, with lead compounds now reaching clinical maturity. Here we describe the mHTT radioligands developed to date and opportunities for further improvement of this radiotracer class.


Subject(s)
Huntingtin Protein , Positron-Emission Tomography , Huntingtin Protein/genetics , Huntingtin Protein/metabolism , Huntingtin Protein/chemistry , Ligands , Humans , Protein Aggregates/drug effects , Mutation , Huntington Disease/diagnostic imaging , Huntington Disease/metabolism , Huntington Disease/genetics , Radiopharmaceuticals/chemistry
10.
J Parkinsons Dis ; 14(4): 657-666, 2024.
Article in English | MEDLINE | ID: mdl-38578902

ABSTRACT

In 2011, the UK medical research charity Cure Parkinson's set up the international Linked Clinical Trials (iLCT) committee to help expedite the clinical testing of potentially disease modifying therapies for Parkinson's disease (PD). The first committee meeting was held at the Van Andel Institute in Grand Rapids, Michigan in 2012. This group of PD experts has subsequently met annually to assess and prioritize agents that may slow the progression of this neurodegenerative condition, using a systematic approach based on preclinical, epidemiological and, where possible, clinical data. Over the last 12 years, 171 unique agents have been evaluated by the iLCT committee, and there have been 21 completed clinical studies and 20 ongoing trials associated with the initiative. In this review, we briefly outline the iLCT process as well as the clinical development and outcomes of some of the top prioritized agents. We also discuss a few of the lessons that have been learnt, and we conclude with a perspective on what the next decade may bring, including the introduction of multi-arm, multi-stage clinical trial platforms and the possibility of combination therapies for PD.


Subject(s)
Clinical Trials as Topic , Parkinson Disease , Humans , Parkinson Disease/drug therapy , Antiparkinson Agents/therapeutic use
11.
Cell Rep ; 43(4): 114031, 2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38583153

ABSTRACT

Outer radial glia (oRG) emerge as cortical progenitor cells that support the development of an enlarged outer subventricular zone (oSVZ) and the expansion of the neocortex. The in vitro generation of oRG is essential to investigate the underlying mechanisms of human neocortical development and expansion. By activating the STAT3 signaling pathway using leukemia inhibitory factor (LIF), which is not expressed in guided cortical organoids, we define a cortical organoid differentiation method from human pluripotent stem cells (hPSCs) that recapitulates the expansion of a progenitor pool into the oSVZ. The oSVZ comprises progenitor cells expressing specific oRG markers such as GFAP, LIFR, and HOPX, closely matching human fetal oRG. Finally, incorporating neural crest-derived LIF-producing cortical pericytes into cortical organoids recapitulates the effects of LIF treatment. These data indicate that increasing the cellular complexity of the organoid microenvironment promotes the emergence of oRG and supports a platform to study oRG in hPSC-derived brain organoids routinely.


Subject(s)
Cell Differentiation , Lateral Ventricles , Leukemia Inhibitory Factor , Organoids , Pluripotent Stem Cells , Humans , Organoids/metabolism , Organoids/cytology , Leukemia Inhibitory Factor/metabolism , Leukemia Inhibitory Factor/pharmacology , Pluripotent Stem Cells/metabolism , Pluripotent Stem Cells/cytology , Lateral Ventricles/cytology , Lateral Ventricles/metabolism , STAT3 Transcription Factor/metabolism , Neuroglia/metabolism , Neuroglia/cytology , Signal Transduction
12.
FEBS J ; 291(12): 2565-2589, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38466799

ABSTRACT

Mutations in FBXO7 have been discovered to be associated with an atypical parkinsonism. We report here a new homozygous missense mutation in a paediatric patient that causes an L250P substitution in the dimerisation domain of Fbxo7. This alteration selectively ablates the Fbxo7-PI31 interaction and causes a significant reduction in Fbxo7 and PI31 levels in patient cells. Consistent with their association with proteasomes, patient fibroblasts have reduced proteasome activity and proteasome subunits. We also show PI31 interacts with the MiD49/51 fission adaptor proteins, and unexpectedly, PI31 acts to facilitate SCFFbxo7-mediated ubiquitination of MiD49. The L250P mutation reduces the SCFFbxo7 ligase-mediated ubiquitination of a subset of its known substrates. Although MiD49/51 expression was reduced in patient cells, there was no effect on the mitochondrial network. However, patient cells show reduced levels of mitochondrial function and mitophagy, higher levels of ROS and are less viable under stress. Our study demonstrates that Fbxo7 and PI31 regulate proteasomes and mitochondria and reveals a new function for PI31 in enhancing the SCFFbxo7 E3 ubiquitin ligase activity.


Subject(s)
F-Box Proteins , Mitochondria , Proteasome Endopeptidase Complex , Ubiquitination , Humans , F-Box Proteins/genetics , F-Box Proteins/metabolism , Proteasome Endopeptidase Complex/metabolism , Proteasome Endopeptidase Complex/genetics , Mitochondria/metabolism , Mitochondria/genetics , Mutation, Missense , Mitophagy/genetics , Fibroblasts/metabolism , Male , HEK293 Cells , Female
13.
Cell Stem Cell ; 31(2): 158-160, 2024 02 01.
Article in English | MEDLINE | ID: mdl-38306992

ABSTRACT

Sham surgery is often required for cell therapies adopting a randomized placebo-controlled double-blinded trial design. Using the case of dopamine neuron therapy for Parkinson's disease, we argue that alternative trial designs should be considered instead, for several reasons relating to ethics, patient burden, ease of unblinding, and cost.


Subject(s)
Cell- and Tissue-Based Therapy , Parkinson Disease , Humans , Dopaminergic Neurons , Parkinson Disease/therapy , Randomized Controlled Trials as Topic
14.
Brain ; 147(6): 1937-1952, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38279949

ABSTRACT

In recent years there has been a renewed interest in the basal forebrain cholinergic system as a target for the treatment of cognitive impairments in patients with Parkinson's disease, due in part to the need to explore novel approaches to treat the cognitive symptoms of the disease and in part to the development of more refined imaging tools that have made it possible to monitor the progressive changes in the structure and function of the basal forebrain system as they evolve over time. In parallel, emerging technologies allowing the derivation of authentic basal forebrain cholinergic neurons from human pluripotent stem cells are providing new powerful tools for the exploration of cholinergic neuron replacement in animal models of Parkinson's disease-like cognitive decline. In this review, we discuss the rationale for cholinergic cell replacement as a potential therapeutic strategy in Parkinson's disease and how this approach can be explored in rodent models of Parkinson's disease-like cognitive decline, building on insights gained from the extensive animal experimental work that was performed in rodent and primate models in the 1980s and 90s. Although therapies targeting the cholinergic system have so far been focused mainly on patients with Alzheimer's disease, Parkinson's disease with dementia may be a more relevant condition. In Parkinson's disease with dementia, the basal forebrain system undergoes progressive degeneration and the magnitude of cholinergic cell loss has been shown to correlate with the level of cognitive impairment. Thus, cell therapy aimed to replace the lost basal forebrain cholinergic neurons represents an interesting strategy to combat some of the major cognitive impairments in patients with Parkinson's disease dementia.


Subject(s)
Basal Forebrain , Cholinergic Neurons , Parkinson Disease , Humans , Basal Forebrain/metabolism , Parkinson Disease/therapy , Parkinson Disease/metabolism , Animals , Cholinergic Neurons/metabolism
16.
Nature ; 2023 Dec 06.
Article in English | MEDLINE | ID: mdl-38057666

ABSTRACT

Human limbs emerge during the fourth post-conception week as mesenchymal buds, which develop into fully formed limbs over the subsequent months1. This process is orchestrated by numerous temporally and spatially restricted gene expression programmes, making congenital alterations in phenotype common2. Decades of work with model organisms have defined the fundamental mechanisms underlying vertebrate limb development, but an in-depth characterization of this process in humans has yet to be performed. Here we detail human embryonic limb development across space and time using single-cell and spatial transcriptomics. We demonstrate extensive diversification of cells from a few multipotent progenitors to myriad differentiated cell states, including several novel cell populations. We uncover two waves of human muscle development, each characterized by different cell states regulated by separate gene expression programmes, and identify musculin (MSC) as a key transcriptional repressor maintaining muscle stem cell identity. Through assembly of multiple anatomically continuous spatial transcriptomic samples using VisiumStitcher, we map cells across a sagittal section of a whole fetal hindlimb. We reveal a clear anatomical segregation between genes linked to brachydactyly and polysyndactyly, and uncover transcriptionally and spatially distinct populations of the mesenchyme in the autopod. Finally, we perform single-cell RNA sequencing on mouse embryonic limbs to facilitate cross-species developmental comparison, finding substantial homology between the two species.

17.
Sci Adv ; 9(44): eadh9543, 2023 11 03.
Article in English | MEDLINE | ID: mdl-37910626

ABSTRACT

The genetic mechanisms underlying the expansion in size and complexity of the human brain remain poorly understood. Long interspersed nuclear element-1 (L1) retrotransposons are a source of divergent genetic information in hominoid genomes, but their importance in physiological functions and their contribution to human brain evolution are largely unknown. Using multiomics profiling, we here demonstrate that L1 promoters are dynamically active in the developing and the adult human brain. L1s generate hundreds of developmentally regulated and cell type-specific transcripts, many that are co-opted as chimeric transcripts or regulatory RNAs. One L1-derived long noncoding RNA, LINC01876, is a human-specific transcript expressed exclusively during brain development. CRISPR interference silencing of LINC01876 results in reduced size of cerebral organoids and premature differentiation of neural progenitors, implicating L1s in human-specific developmental processes. In summary, our results demonstrate that L1-derived transcripts provide a previously undescribed layer of primate- and human-specific transcriptome complexity that contributes to the functional diversification of the human brain.


Subject(s)
Retroelements , Transcriptome , Animals , Humans , Retroelements/genetics , Long Interspersed Nucleotide Elements/genetics , Neurons , Primates/genetics
18.
bioRxiv ; 2023 Oct 27.
Article in English | MEDLINE | ID: mdl-37986877

ABSTRACT

T cells develop from circulating precursors, which enter the thymus and migrate throughout specialised sub-compartments to support maturation and selection. This process starts already in early fetal development and is highly active until the involution of the thymus in adolescence. To map the micro-anatomical underpinnings of this process in pre- vs. post-natal states, we undertook a spatially resolved analysis and established a new quantitative morphological framework for the thymus, the Cortico-Medullary Axis. Using this axis in conjunction with the curation of a multimodal single-cell, spatial transcriptomics and high-resolution multiplex imaging atlas, we show that canonical thymocyte trajectories and thymic epithelial cells are highly organised and fully established by post-conception week 12, pinpoint TEC progenitor states, find that TEC subsets and peripheral tissue genes are associated with Hassall's Corpuscles and uncover divergence in the pace and drivers of medullary entry between CD4 vs. CD8 T cell lineages. These findings are complemented with a holistic toolkit for spatial analysis and annotation, providing a basis for a detailed understanding of T lymphocyte development.

19.
PLoS One ; 18(10): e0292180, 2023.
Article in English | MEDLINE | ID: mdl-37788254

ABSTRACT

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.


Subject(s)
Parkinson Disease , Humans , Parkinson Disease/genetics , Parkinson Disease/therapy , Palliative Care
20.
Cell Stem Cell ; 30(10): 1299-1314.e9, 2023 10 05.
Article in English | MEDLINE | ID: mdl-37802036

ABSTRACT

Cell replacement therapies for Parkinson's disease (PD) based on transplantation of pluripotent stem cell-derived dopaminergic neurons are now entering clinical trials. Here, we present quality, safety, and efficacy data supporting the first-in-human STEM-PD phase I/IIa clinical trial along with the trial design. The STEM-PD product was manufactured under GMP and quality tested in vitro and in vivo to meet regulatory requirements. Importantly, no adverse effects were observed upon testing of the product in a 39-week rat GLP safety study for toxicity, tumorigenicity, and biodistribution, and a non-GLP efficacy study confirmed that the transplanted cells mediated full functional recovery in a pre-clinical rat model of PD. We further observed highly comparable efficacy results between two different GMP batches, verifying that the product can be serially manufactured. A fully in vivo-tested batch of STEM-PD is now being used in a clinical trial of 8 patients with moderate PD, initiated in 2022.


Subject(s)
Human Embryonic Stem Cells , Parkinson Disease , Humans , Rats , Animals , Parkinson Disease/therapy , Tissue Distribution , Cell Differentiation/physiology , Stem Cell Transplantation/methods , Dopaminergic Neurons/physiology
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