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Huntington's disease is classically described as a neurodegenerative disorder of monogenic aetiology. The disease is characterized by an abnormal polyglutamine expansion in the huntingtin gene, which drives the toxicity of the mutated form of the protein. However, accumulation of the microtubule-associated protein tau, which is involved in a number of neurological disorders, has also been observed in patients with Huntington's disease. In order to unravel the contribution of tau hyperphosphorylation to hallmark features of Huntington's disease, we administered weekly intraperitoneal injections of the anti-tau pS202 CP13 monoclonal antibody to zQ175 mice and characterized the resulting behavioral and biochemical changes. After 12 weeks of treatment, motor impairments, cognitive performance and general health were improved in zQ175 mice along with a significant reduction in hippocampal pS202 tau levels. Despite the lack of effect of CP13 on neuronal markers associated with Huntington's disease pathology, tau-targeting enzymes and gliosis, CP13 was shown to directly impact mutant huntingtin aggregation such that brain levels of amyloid fibrils and huntingtin oligomers were decreased, while larger huntingtin protein aggregates were increased. Investigation of CP13 treatment of Huntington's disease patient-derived induced pluripotent stem cells (iPSCs) revealed a reduction in pS202 levels in differentiated cortical neurons and a rescue of neurite length. Collectively, these findings suggest that attenuating tau pathology could mitigate behavioral and molecular hallmarks associated with Huntington's disease.

Neurodegenerative disorders emerge from the failure of intricate cellular mechanisms, which ultimately lead to the loss of vulnerable neuronal populations. Research conducted across several laboratories has now provided compelling evidence that pathogenic proteins can also contribute to non-cell autonomous toxicity in several neurodegenerative contexts, including Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as Amyotrophic Lateral Sclerosis. Given the nearly ubiquitous nature of abnormal protein accumulation in such disorders, elucidating the mechanisms and routes underlying these processes is essential to the development of effective treatments. To this end, physiologically relevant human in vitro models are critical to understand the processes surrounding uptake, release and nucleation under physiological or pathological conditions. This review explores the use of human-induced pluripotent stem cells (iPSCs) to study prion-like protein propagation in neurodegenerative diseases, discusses advantages and limitations of this model, and presents emerging technologies that, combined with the use of iPSC-based models, will provide powerful model systems to propel fundamental research forward.

If theories postulating that pathological proteins associated with neurodegenerative disorders behave similarly to prions were initially viewed with reluctance, it is now well-accepted that this occurs in several disease contexts. Notably, it has been reported that protein misfolding and subsequent prion-like properties can actively participate in neurodegenerative disorders. While this has been demonstrated in multiple cellular and animal model systems related to Alzheimer’s and Parkinson’s diseases, the prion-like properties of the mutant huntingtin protein (mHTT), associated with Huntington’s disease (HD), have only recently been considered to play a role in this pathology, a concept our research group has contributed to extensively. In this review, we summarize the last few years of in vivo research in the field and speculate on the relationship between prion-like events and human HD. By interpreting observations primarily collected in in vivo models, our discussion will aim to discriminate which experimental factors contribute to the most efficient types of prion-like activities of mHTT and which routes of propagation may be more relevant to the human condition. A look back at nearly a decade of experimentation will inform future research and whether therapeutic strategies may emerge from this new knowledge.

The production of extracellular vesicles (EV) is a ubiquitous feature of eukaryotic cells but pathological events can affect their formation and constituents. We sought to characterize the nature, profile and protein signature of EV in the plasma of Parkinson's disease (PD) patients and how they correlate to clinical measures of the disease. EV were initially collected from cohorts of PD (n = 60; Controls, n = 37) and Huntington's disease (HD) patients (Pre-manifest, n = 11; manifest, n = 52; Controls, n = 55) – for comparative purposes in individuals with another chronic neurodegenerative condition – and exhaustively analyzed using flow cytometry, electron microscopy and proteomics. We then collected 42 samples from an additional independent cohort of PD patients to confirm our initial results. Through a series of iterative steps, we optimized an approach for defining the EV signature in PD. We found that the number of EV derived specifically from erythrocytes segregated with UPDRS scores corresponding to different disease stages. Proteomic analysis further revealed that there is a specific signature of proteins that could reliably differentiate control subjects from mild and moderate PD patients. Taken together, we have developed/identified an EV blood-based assay that has the potential to be used as a biomarker for PD.

Huntington’s disease (HD) is a hereditary disorder that typically manifests in adulthood with a combination of motor, cognitive and psychiatric problems. The pathology is caused by a mutation in the huntingtin gene which results in the production of an abnormal protein, mutant huntingtin (mHtt). This protein is ubiquitously expressed and known to confer toxicity to multiple cell types. We have recently reported that HD brains are also characterised by vascular abnormalities, which include changes in blood vessel density/diameter as well as increased blood–brain barrier (BBB) leakage.ObjectivesSeeking to elucidate the origin of these vascular and BBB abnormalities, we studied platelets that are known to play a role in maintaining the integrity of the vasculature and thrombotic pathways linked to this, given they surprisingly contain the highest concentration of mHtt of all blood cells.MethodsWe assessed the functional status of platelets by performing ELISA, western blot and RNA sequencing in a cohort of 71 patients and 68 age- and sex-matched healthy control subjects. We further performed haemostasis and platelet depletion tests in the R6/2 HD mouse model.ResultsOur findings indicate that the platelets in HD are dysfunctional with respect to the release of angiogenic factors and functions including thrombosis, angiogenesis and vascular haemostasis.ConclusionTaken together, our results provide a better understanding for the impact of mHtt on platelet function.

The production and release of extracellular vesicles (EV) is a property shared by all eukaryotic cells and a phenomenon frequently exacerbated in pathological conditions. The protein cargo of EV, their cell type signature and availability in bodily fluids make them particularly appealing as biomarkers. We recently demonstrated that platelets, among all types of blood cells, contain the highest concentrations of the mutant huntingtin protein (mHtt)-the genetic product of Huntington's disease (HD), a neurodegenerative disorder which manifests in adulthood with a complex combination of motor, cognitive and psychiatric deficits. Herein, we used a cohort of 59 HD patients at all stages of the disease, including individuals in pre-manifest stages, and 54 healthy age- and sex-matched controls, to evaluate the potential of EV derived from platelets as a biomarker. We found that platelets of pre-manifest and manifest HD patients do not release more EV even if they are activated. Importantly, mHtt was not found within EV derived from platelets, despite them containing high levels of this protein. Correlation analyses also failed to reveal an association between the number of platelet-derived EV and the age of the patients, the number of CAG repeats, the Unified Huntington Disease Rating Scale total motor score, the Total Functional Capacity score or the Burden of Disease score. Our data would, therefore, suggest that EV derived from platelets with HD is not a valuable biomarker in HD.

There is compelling evidence that the pathophysiology of many neurodegenerative diseases includes dysregulation of the immune system, with some elements that precede disease onset. However, if these alterations are prominent, why have clinical trials targeting this system failed to translate into long-lasting meaningful benefits for patients? This review focuses on Huntington's disease, a genetic disorder marked by notable cerebral and peripheral inflammation. We summarize ongoing and completed clinical trials that have involved pharmacological approaches to inhibit various components of the immune system and their pre-clinical correlates. We then discuss new putative treatment strategies using more targeted immunotherapies such as vaccination and intrabodies and how these may offer new hope in the treatment of Huntington's disease as well as other neurodegenerative diseases.

The types of treatments and interventions being developed for chronic neurodegenerative disorders have expanded considerably in recent years. In addition to the variety of targets being pursued, strategies have moved from symptom management to more directed disease-modifying approaches. Among them are antibody-based therapies, which are not only being evaluated for a range of tauopathies and synucleinopathies, but are also emerging as a potential application for monogenic disorders of the central nervous system (CNS), including Huntington's disease (HD). Despite the excitement around the early trial data of anti-sense oligonucleotides (ASO) treatment for such disorders, antibody therapies may hold the key to tackling another aspect of the disease that could be critical to its pathogenesis. While gene-based methodologies are designed to lower, predominantly within cellular elements, mutant huntingtin protein (mHtt) - the genetic product of HD - the pathological protein is abundant in free forms and in several compartments including the cerebrospinal fluid, the plasma and the extracellular matrix. With accumulating evidence for the spreading and seeding capacities of mHtt, it may indeed be essential to target the protein both intracellularly and extracellularly. Therefore, free forms of mHtt not only represents an ideal target for antibodies, but one that needs to be addressed if meaningful and maximal clinical benefits are to be expected. This review explores the potential use of antibody-based therapies to treat HD, including the rationale for this approach as well as the pre-clinical data supporting it. The potential challenges that will need to be considered if such route is to be pursued clinically are also discussed.

To date, medical and surgical interventions offered to patients with Parkinson's disease (PD) serve only to manage clinical symptoms; they have not shown the capacity to halt nor reverse degenerative processes. There is therefore an urgent need to identify and/or develop therapeutic strategies that will demonstrate 'disease modifying' capacities. The molecule cystamine, and its reduced form cysteamine, act via a number of pathways determined to be critical to the pathogenesis of PD. In particular, cystamine is capable of crossing the blood-brain barrier, and both agents (cystamine and cysteamine) can promote the secretion of neurotrophic factors, inhibit oxidative stress, reduce inflammatory responses and importantly, have already been trialed in humans for a number of other clinical indications. In the last decade, our laboratory has accumulated compelling evidence that both cystamine and cysteamine can halt, and even reverse, ongoing neurodegenerative processes in a number of different models of PD, and as such, should now be taken forward to clinical trials in PD.

In recent years, evidence has accumulated to suggest that mutant huntingtin protein (mHTT) can spread into healthy tissue in a prion-like fashion. This theory, however, remains controversial. To fully address this concept and to understand the possible consequences of mHTT spreading to Huntington’s disease pathology, we investigated the effects of exogenous human fibrillar mHTT (Q48) and huntingtin (HTT) (Q25) N-terminal fragments in three cellular models and three distinct animal paradigms. For in vitro experiments, human neuronal cells [induced pluripotent stem cell-derived GABA neurons (iGABA) and (SH-SY5Y)] as well as human THP1-derived macrophages, were incubated with recombinant mHTT fibrils. Recombinant mHTT and HTT fibrils were taken up by all cell types, inducing cell morphology changes and death. Variations in HTT aggregation were further observed following incubation with fibrils in both THP1 and SH-SY5Y cells. For in vivo experiments, adult wild-type (WT) mice received a unilateral intracerebral cortical injection and R6/2 and WT pups were administered fibrils via bilateral intraventricular injections. In both protocols, the injection of Q48 fibrils resulted in cognitive deficits and increased anxiety-like behavior. Post-mortem analysis of adult WT mice indicated that most fibrils had been degraded/cleared from the brain by 14 months post-surgery. Despite the absence of fibrils at these later time points, a change in the staining pattern of endogenous HTT was detected. A similar change was revealed in post-mortem analysis of the R6/2 mice. These effects were specific to central administration of fibrils, as mice receiving intravenous injections were not characterized by behavioral changes. In fact, peripheral administration resulted in an immune response mounting against the fibrils. Together, the in vitro and in vivo data indicate that exogenously administered mHTT is capable of both causing and exacerbating disease pathology. Electronic supplementary material The online version of this article (10.1007/s00401-019-01973-6) contains supplementary material, which is available to authorized users.

Neurodegenerative disorders emerge from the failure of intricate cellular mechanisms, which ultimately lead to the loss of vulnerable neuronal populations. Research conducted across several laboratories has now provided compelling evidence that pathogenic proteins can also contribute to non-cell autonomous toxicity in several neurodegenerative contexts, including Alzheimer's, Parkinson's, and Huntington's diseases as well as Amyotrophic Lateral Sclerosis. Given the nearly ubiquitous nature of abnormal protein accumulation in such disorders, elucidating the mechanisms and routes underlying these processes is essential to the development of effective treatments. To this end, physiologically relevant human in vitro models are critical to understand the processes surrounding uptake, release and nucleation under physiological or pathological conditions. This review explores the use of human-induced pluripotent stem cells (iPSCs) to study prion-like protein propagation in neurodegenerative diseases, discusses advantages and limitations of this model, and presents emerging technologies that, combined with the use of iPSC-based models, will provide powerful model systems to propel fundamental research forward.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.