scholarly journals What, When and How to Measure—Peripheral Biomarkers in Therapy of Huntington’s Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 1561
Author(s):  
Lukasz Przybyl ◽  
Magdalena Wozna-Wysocka ◽  
Emilia Kozlowska ◽  
Agnieszka Fiszer
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Motor Deficits ◽  
Or Efficiency ◽  
Peripheral Tissues ◽  
Disease Symptoms ◽  
The Central Nervous System ◽  
Inflammatory Proteins ◽  
Scientific Attention

Among the main challenges in further advancing therapeutic strategies for Huntington’s disease (HD) is the development of biomarkers which must be applied to assess the efficiency of the treatment. HD is a dreadful neurodegenerative disorder which has its source of pathogenesis in the central nervous system (CNS) but is reflected by symptoms in the periphery. Visible symptoms include motor deficits and slight changes in peripheral tissues, which can be used as hallmarks for prognosis of the course of HD, e.g., the onset of the disease symptoms. Knowing how the pathology develops in the context of whole organisms is crucial for the development of therapy which would be the most beneficial for patients, as well as for proposing appropriate biomarkers to monitor disease progression and/or efficiency of treatment. We focus here on molecular peripheral biomarkers which could be used as a measurable outcome of potential therapy. We present and discuss a list of wet biomarkers which have been proposed in recent years to measure pre- and postsymptomatic HD. Interestingly, investigation of peripheral biomarkers in HD can unravel new aspects of the disease pathogenesis. This especially refers to inflammatory proteins or specific immune cells which attract scientific attention in neurodegenerative disorders.

scholarly journals Insights into kinetics, release, and behavioral effects of brain-targeted hybrid nanoparticles for cholesterol delivery in Huntington’s disease

2020 ◽  
Author(s):  
Giulia Birolini ◽  
Marta Valenza ◽  
Ilaria Ottonelli ◽  
Alice Passoni ◽  
Monica Favagrossa ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Polymeric Nanoparticles ◽  
Cholesterol Biosynthesis ◽  
Hybrid Nanoparticles ◽  
Neural Cells ◽  
Peripheral Tissues ◽  
Brain Cholesterol ◽  
The Brain

AbstractSupplementing brain cholesterol is emerging as a potential treatment for Huntington’s disease (HD), a genetic neurodegenerative disorder characterized, among other abnormalities, by inefficient brain cholesterol biosynthesis. However, delivering cholesterol to the brain is challenging due to the bloodbrain barrier (BBB), which prevents it from reaching the striatum, especially, with therapeutically relevant doses.Here we describe the distribution, kinetics, release, and safety of novel hybrid polymeric nanoparticles made of PLGA and cholesterol which were modified with an heptapeptide (g7) for BBB transit (hybrid-g7-NPs-chol). We show that these NPs rapidly reach the brain and target neural cells. Moreover, deuterium-labeled cholesterol from hybrid-g7-NPs-chol is released in a controlled manner within the brain and accumulates over time, while being rapidly removed from peripheral tissues and plasma. We confirm that systemic and repeated injections of the new hybrid-g7-NPs-chol enhanced endogenous cholesterol biosynthesis, prevented cognitive decline, and ameliorated motor defects in HD animals, without any inflammatory reaction.In summary, this study provides insights about the benefits and safety of cholesterol delivery through advanced brain-permeable nanoparticles for HD treatment.

scholarly journals Levels of Interleukin-6 in Saliva, but Not Plasma, Correlate with Clinical Metrics in Huntington’s Disease Patients and Healthy Control Subjects

2020 ◽  
Vol 21 (17) ◽  
pp. 6363 ◽  
Author(s):  
Jody Corey-Bloom ◽  
Ryan S. Fischer ◽  
Aeri Kim ◽  
Chase Snell ◽  
Georgia M. Parkin ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Interleukin 6 ◽  
Inflammatory Responses ◽  
Neurodegenerative Disorder ◽  
Interleukin 1 ◽  
Peripheral Tissues ◽  
Reactive Protein ◽  
Control Subjects ◽  
Healthy Control

Growing evidence suggests that inflammatory responses, in both the brain and peripheral tissues, contribute to disease pathology in Huntington’s disease (HD), an inherited, progressive neurodegenerative disorder typically affecting adults in their 30–40 s. Hence, studies of inflammation-related markers in peripheral fluids might be useful to better characterize disease features. In this study, we measured levels of C-reactive protein (CRP), Interleukin-6 (IL-6), interleukin 1 beta (IL-1B), and alpha-amylase (AA) in saliva and plasma from n = 125 subjects, including n = 37 manifest HD patients, n = 36 premanifest patients, and n = 52 healthy controls, using immunoassays. We found increases in salivary levels of IL-6, IL-1B and CRP across different disease groups and increased levels of IL-6 in the plasma of HD patients as compared to premanifest patients and controls. The levels of salivary IL-6 were significantly correlated with each of the other salivary markers, as well as with IL-6 levels measured in plasma. Further, salivary IL-6 and IL-1B levels were significantly positively correlated with Total Motor Score (TMS) and chorea scores and negatively correlated with Total Functional Capacity (TFC) in HD patients, whereby in healthy control subjects, IL-6 was significantly negatively correlated with Montreal Cognitive Assessment (MoCA) and the Symbol Digit Modalities test (SDM). Interestingly, the plasma levels of IL-6 did not show similar correlations to any clinical measures in either HD or control subjects. These findings suggest that salivary IL-6 is particularly relevant as a potential non-invasive biomarker for HD symptoms. The advent of an effective, dependable salivary biomarker would meet the urgent need for a less invasive means of identifying and monitoring HD disease progression.

scholarly journals SorCS2 dynamically interacts with TrkB and GluN2B to control neurotransmission and Huntington's disease progression

2021 ◽  
Author(s):  
Alena Salašová ◽  
Niels Sanderhoff Degn ◽  
Mikhail Paveliev ◽  
Niels Kjaergaard Madsen ◽  
Saray Benito ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Progression ◽  
Neurodegenerative Disorder ◽  
Dorsal Striatum ◽  
Long Term Potentiation ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Bdnf Expression ◽  
Term Potentiation

Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor dysfunction and loss of medium spiny neurons (MSNs) in dorsal striatum. Brain-derived neurotrophic factor (BDNF) sustains functionality and integrity of MSNs, and thus reduced BDNF signaling is integral to the disease. Here we show that SorCS2 is expressed in MSNs with reduced expression in R6/1 HD model, and that SorCS2 deficiency exacerbates the disease progression in R6/1 mice. Furthermore, we find that SorCS2 binds TrkB and the NMDA receptor subunit GluN2B, which is required to control neurotransmission in corticostriatal synapses. While BDNF stimulates SorCS2-TrkB complex formation to enable TrkB signaling, it disengages SorCS2 from GluN2B, leading to enrichment of the subunit at postsynaptic densities. Consequently, long-term potentiation (LTP) is abolished in SorCS2 deficient mice, despite increased striatal TrkB and unaltered BDNF expression. In contrast, the addition of exogenous BDNF rescues the phenotype. Finally, GluN2B, but not GluN2A, currents are also severely impaired in the SorCS2 KO mice. To conclude, we uncovered that SorCS2 dynamically targets TrkB and GluN2B to orchestrate BDNF-dependent plasticity in MSNs of dorsal striatum. We propose that SorCS2 deficiency impairs MSN function thereby increasing neuronal vulnerability and accelerating the motor deficits in Huntington's disease.

scholarly journals Neuroimmunology of Huntington’s Disease: Revisiting Evidence from Human Studies

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Natalia P. Rocha ◽  
Fabiola M. Ribeiro ◽  
Erin Furr-Stimming ◽  
Antonio L. Teixeira
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Genetic Disorder ◽  
Cag Repeat ◽  
Motor Dysfunction ◽  
Gene Encoding ◽  
Ultimate Cause ◽  
The Central Nervous System ◽  
Inflammatory Changes

Huntington’s disease (HD) is a neurodegenerative disorder characterized by selective loss of neurons in the striatum and cortex, which leads to progressive motor dysfunction, cognitive decline, and psychiatric disorders. Although the cause of HD is well described—HD is a genetic disorder caused by a trinucleotide (CAG) repeat expansion in the gene encoding for huntingtin (HTT) on chromosome 4p16.3—the ultimate cause of neuronal death is still uncertain. Apart from impairment in systems for handling abnormal proteins, other metabolic pathways and mechanisms might contribute to neurodegeneration and progression of HD. Among these, inflammation seems to play a role in HD pathogenesis. The current review summarizes the available evidence about immune and/or inflammatory changes in HD. HD is associated with increased inflammatory mediators in both the central nervous system and periphery. Accordingly, there have been some attempts to slow HD progression targeting the immune system.

scholarly journals Establishment and maintenance of an R6/1 transgenic mouse colony and validation of its progressive neurological phenotype to study Huntington’s disease

2018 ◽  
Vol 5 (1) ◽  
Author(s):  
Lucía Gabriela García-Lara ◽  
Adriana Morales-Martínez ◽  
Quetzalli Denisse Angeles-López ◽  
Hilda Pedraza-Espitia ◽  
Iván Pérez-Neri ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Transgenic Mouse ◽  
Neurodegenerative Disorder ◽  
Transgenic Animal ◽  
Phenotypic Characteristics ◽  
Neurological Phenotype ◽  
Transgenic Animal Models ◽  
The Central Nervous System

Huntington’s disease (HD) is a hereditary neurodegenerative disorder of the central nervous system that mainly affects the basal ganglia and has no cure. The mutation is located at an abnormal expansion of the CAG triplet in the Huntingtin gene. Humans show psychiatric, behavioural and motor disorders. Transgenic animal models are essential to the study of HD since the disease only affects humans. Therefore, the aim of this article was to describe the formation and maintenance of and to validate the progressive neurological phenotype of an R6/1 transgenic mouse colony. To achieve our objective, the colony founder was imported from Jackson Laboratories, and the mice were kept under controlled environmental conditions. The animals were bred at the vivarium of the Instituto Nacional de Neurología y Neurocirugía Man­uel Velasco Suárez. The R6/1 transgenic mice were successfully bred and showed genetic and phenotypic characteristics similar to the ones previously reported. Our colony is currently established and validated with the condi­tions of our vivarium and has produced more than four generations of R6/1 mice. The establishment of the R6/1 colony and its maintenance through generation is an advantage since it allows us to follow the authenticity of the transgenic mice regarding their phenotypic and motor behaviours. Fur­thermore, these animals can be compared with other transgenic mice that reproduce some of the main characteristics of the disease manifested in hu­mans, making these transgenic R6/1 mice a useful tool for the study of HD.

scholarly journals Cognitive Deficits in the R6/2 mouse model of Huntington’s disease and their Amelioration with Donepezil

2014 ◽  
Vol 27 (3) ◽  
Author(s):  
Carol A. Murphy ◽  
Neil E. Paterson ◽  
Angela Chen ◽  
Washington Arias ◽  
Dansha He ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Psychiatric Symptoms ◽  
Motor Dysfunction ◽  
Cag Repeats ◽  
Motor Deficits ◽  
Cholinergic Function ◽  
Severe Motor

The neurodegenerative disorder Huntington’s disease (HD) is characterized by motor dysfunction, cognitive impairment and psychiatric symptoms. The R6/2 (120 CAG repeats) mouse model of HD recapitulates many of the symptoms of the disease, including marked impairments in cognition and severe motor deficits. As cholinergic function has been reported to be affected in both HD patients and this mouse model, we tested whether treatment with the cholinesterase inhibitor donepezil could improve the R6/2 mice performance in the two-choice swim tank visual discrimination and reversal task. In this test mice are trained to swim towards a light cued platform located on one side of a water-filled tank. Once mice reach an acquisition criterion a reversal ensues. Wild-type and R6/2 mice were dosed with donepezil (0.6 mg/kg/day) or vehicle starting at 8 weeks of age and tested starting at 9 weeks of age. In experiment 1, vehicle-treated R6/2 mice showed a significant deficit during acquisition and reversal as compared to vehicle-treated WT mice. Donepezil improved reversal in the R6/2 group. In experiment 2, we confirmed the beneficial effect of donepezil on reversal in similar conditions. Donepezil had no effect on activity as measured in the open field test or through the latency to reach the platform during the swim test. We suggest that the donepezil-induced improvements in cognitive function observed in the R6/2 transgenic model of HD may reflect amelioration of deficits in cholinergic function that have been reported previously in this model. Further work is required to confirm the findings of these interesting although preliminary studies.

scholarly journals Emerging Roles of Exosomes in Huntington’s Disease

2021 ◽  
Vol 22 (8) ◽  
pp. 4085
Author(s):  
Hanadi Ananbeh ◽  
Petr Vodicka ◽  
Helena Kupcova Skalnikova
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Cell Types ◽  
Neuroprotective Effects ◽  
The Central Nervous System

Huntington’s disease (HD) is a rare hereditary autosomal dominant neurodegenerative disorder, which is caused by expression of mutant huntingtin protein (mHTT) with an abnormal number of glutamine repeats in its N terminus, and characterized by intracellular mHTT aggregates (inclusions) in the brain. Exosomes are small extracellular vesicles that are secreted generally by all cell types and can be isolated from almost all body fluids such as blood, urine, saliva, and cerebrospinal fluid. Exosomes may participate in the spreading of toxic misfolded proteins across the central nervous system in neurodegenerative diseases. In HD, such propagation of mHTT was observed both in vitro and in vivo. On the other hand, exosomes might carry molecules with neuroprotective effects. In addition, due to their capability to cross blood-brain barrier, exosomes hold great potential as sources of biomarkers available from periphery or carriers of therapeutics into the central nervous system. In this review, we discuss the emerging roles of exosomes in HD pathogenesis, diagnosis, and therapy.

scholarly journals Protein kinase CK2 alpha prime and alpha-synuclein constitute a key regulatory pathway in Huntington’s disease

2020 ◽  
Author(s):  
Dahyun Yu ◽  
Nicole Zarate ◽  
Francesco Cuccu ◽  
Johnny S. Yue ◽  
Taylor G. Brown ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein Kinase Ck2 ◽  
Neurodegenerative Disorder ◽  
Alpha Synuclein ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Striatal Neurons ◽  
Kinase Ck2

SummaryHuntington’s Disease (HD) is a neurodegenerative disorder caused by a polyglutamine expansion in the HTT protein. This mutation causes HTT misfolding and aggregation, preferentially affecting neurons of the basal ganglia. Other aggregation-prone proteins like alpha-synuclein (α-syn), mostly associated with Parkinson’s disease (PD), has recently been involved in motor deficits in HD, but its mechanism of action is unknown. Here we showed that α-syn serine 129 phosphorylation (α-syn-pS129), a posttranslational modification linked to α-synucleinopathy, is highly phosphorylated in the brain of symptomatic zQ175 HD mice. We demonstrated that such phosphorylation is mediated by Protein Kinase CK2 alpha prime (CK2α’), which is preferentially induced in striatal neurons in HD. Knocking out one allele of CK2α’ in zQ175 mice decreased α-syn-pS129 in the striatum and ameliorated several HD-like symptoms including neuroinflammation, transcriptional alterations, excitatory synaptic transmission deficits and motor dysfunction. Our data suggests CK2α’-mediated synucleinopathy as a key molecular mechanism of neurodegeneration in HD.

scholarly journals HTT silencing delays onset and slows progression of Huntington’s disease like phenotype: Monitoring with a novel neurovascular biomarker

2020 ◽  
Author(s):  
Hongshuai Liu ◽  
Chuangchuang Zhang ◽  
Jiadi Xu ◽  
Jing Jin ◽  
Liam Cheng ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Functional Neuroimaging ◽  
Motor Deficits ◽  
Striatal Neurons ◽  
Gene Coding ◽  
Allele Specific ◽  
Noninvasive Biomarkers

AbstractHuntington’s disease (HD) is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene, coding for pathologic mutant HTT protein (mHTT). Because of its gain-of-function mechanism and monogenic etiology, strategies to lower HTT are being actively investigated as disease-modifying therapies. Most approaches are currently targeted at the manifest HD stage, when clinical outcomes are used to evaluate the effectiveness of therapy. However, as almost 50% of striatal volume has been lost at the time of onset of manifest HD it would be preferable to begin therapy in the premanifest period. An unmet challenge is how to evaluate therapeutic efficacy before the presence of clinical symptoms as outcome measures. To address this, we have been developing more sensitive biomarkers such as functional neuroimaging with the goal of identifying noninvasive biomarkers that provide insight into the best time to introduce HTT-lowering treatment. In this study, we mapped the temporal trajectories of arteriolar cerebral blood volumes (CBVa) using inflow-based vascular-space-occupancy (iVASO) MRI technique in an HD mouse model. Significantly elevated CBVa was evident in premanifest zQ175 HD mice prior to motor deficits and striatal atrophy, recapitulating altered CBVa in human premanifest HD. CRISPR/Cas9-mediated non-allele-specific HTT silencing in striatal neurons restored altered CBVa in premanifest zQ175 mice, delayed onset of striatal atrophy, and slowed the progression of motor phenotype and brain pathology. This study showed the potential of CBVa as a noninvasive fMRI biomarker for premanifest HD clinical trials and demonstrates long-term benefits of introducing an HTT lowering treatment in the premanifest HD.

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