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1.
Acta Neuropathol Commun ; 12(1): 88, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38840253

ABSTRACT

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the coding sequence of huntingtin protein. Initially, it predominantly affects medium-sized spiny neurons (MSSNs) of the corpus striatum. No effective treatment is still available, thus urging the identification of potential therapeutic targets. While evidence of mitochondrial structural alterations in HD exists, previous studies mainly employed 2D approaches and were performed outside the strictly native brain context. In this study, we adopted a novel multiscale approach to conduct a comprehensive 3D in situ structural analysis of mitochondrial disturbances in a mouse model of HD. We investigated MSSNs within brain tissue under optimal structural conditions utilizing state-of-the-art 3D imaging technologies, specifically FIB/SEM for the complete imaging of neuronal somas and Electron Tomography for detailed morphological examination, and image processing-based quantitative analysis. Our findings suggest a disruption of the mitochondrial network towards fragmentation in HD. The network of interlaced, slim and long mitochondria observed in healthy conditions transforms into isolated, swollen and short entities, with internal cristae disorganization, cavities and abnormally large matrix granules.


Subject(s)
Disease Models, Animal , Huntington Disease , Imaging, Three-Dimensional , Mitochondria , Animals , Huntington Disease/pathology , Huntington Disease/genetics , Huntington Disease/metabolism , Mitochondria/ultrastructure , Mitochondria/pathology , Mitochondria/metabolism , Imaging, Three-Dimensional/methods , Mice , Mice, Transgenic , Brain/pathology , Brain/ultrastructure , Brain/metabolism , Microscopy, Electron/methods , Male , Neurons/pathology , Neurons/ultrastructure , Neurons/metabolism
2.
Mol Cell ; 84(10): 1980-1994.e8, 2024 May 16.
Article in English | MEDLINE | ID: mdl-38759629

ABSTRACT

Aggregation of proteins containing expanded polyglutamine (polyQ) repeats is the cytopathologic hallmark of a group of dominantly inherited neurodegenerative diseases, including Huntington's disease (HD). Huntingtin (Htt), the disease protein of HD, forms amyloid-like fibrils by liquid-to-solid phase transition. Macroautophagy has been proposed to clear polyQ aggregates, but the efficiency of aggrephagy is limited. Here, we used cryo-electron tomography to visualize the interactions of autophagosomes with polyQ aggregates in cultured cells in situ. We found that an amorphous aggregate phase exists next to the radially organized polyQ fibrils. Autophagosomes preferentially engulfed this amorphous material, mediated by interactions between the autophagy receptor p62/SQSTM1 and the non-fibrillar aggregate surface. In contrast, amyloid fibrils excluded p62 and evaded clearance, resulting in trapping of autophagic structures. These results suggest that the limited efficiency of autophagy in clearing polyQ aggregates is due to the inability of autophagosomes to interact productively with the non-deformable, fibrillar disease aggregates.


Subject(s)
Amyloid , Autophagosomes , Autophagy , Huntingtin Protein , Huntington Disease , Peptides , Protein Aggregates , Sequestosome-1 Protein , Peptides/metabolism , Peptides/chemistry , Peptides/genetics , Humans , Huntingtin Protein/metabolism , Huntingtin Protein/genetics , Huntingtin Protein/chemistry , Autophagosomes/metabolism , Autophagosomes/ultrastructure , Sequestosome-1 Protein/metabolism , Sequestosome-1 Protein/genetics , Amyloid/metabolism , Amyloid/chemistry , Amyloid/genetics , Huntington Disease/metabolism , Huntington Disease/genetics , Huntington Disease/pathology , Cryoelectron Microscopy , Animals , Protein Aggregation, Pathological/metabolism , Protein Aggregation, Pathological/genetics
3.
Cell Death Dis ; 15(5): 337, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38744826

ABSTRACT

Huntington's disease (HD) is a monogenic neurodegenerative disease, caused by the CAG trinucleotide repeat expansion in exon 1 of the Huntingtin (HTT) gene. The HTT gene encodes a large protein known to interact with many proteins. Huntingtin-associated protein 40 (HAP40) is one that shows high binding affinity with HTT and functions to maintain HTT conformation in vitro. However, the potential role of HAP40 in HD pathogenesis remains unknown. In this study, we found that the expression level of HAP40 is in parallel with HTT but inversely correlates with mutant HTT aggregates in mouse brains. Depletion of endogenous HAP40 in the striatum of HD140Q knock-in (KI) mice leads to enhanced mutant HTT aggregation and neuronal loss. Consistently, overexpression of HAP40 in the striatum of HD140Q KI mice reduced mutant HTT aggregation and ameliorated the behavioral deficits. Mechanistically, HAP40 preferentially binds to mutant HTT and promotes Lysine 48-linked ubiquitination of mutant HTT. Our results revealed that HAP40 is an important regulator of HTT protein homeostasis in vivo and hinted at HAP40 as a therapeutic target in HD treatment.


Subject(s)
Huntingtin Protein , Huntington Disease , Animals , Huntington Disease/metabolism , Huntington Disease/genetics , Huntington Disease/pathology , Huntingtin Protein/metabolism , Huntingtin Protein/genetics , Mice , Humans , Disease Models, Animal , Ubiquitination , Protein Aggregation, Pathological/genetics , Protein Aggregation, Pathological/metabolism , Mutation , Protein Aggregates , Mice, Transgenic , Corpus Striatum/metabolism , Corpus Striatum/pathology , Neurons/metabolism , Neurons/pathology
4.
Sci Adv ; 10(20): eadl2036, 2024 May 17.
Article in English | MEDLINE | ID: mdl-38758800

ABSTRACT

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by preferential neuronal loss in the striatum. The mechanism underlying striatal selective neurodegeneration remains unclear, making it difficult to develop effective treatments for HD. In the brains of nonhuman primates, we examined the expression of Huntingtin (HTT), the gene responsible for HD. We found that HTT protein is highly expressed in striatal neurons due to its slow degradation in the striatum. We also identified tripartite motif-containing 37 (TRIM37) as a primate-specific protein that interacts with HTT and is selectively reduced in the primate striatum. TRIM37 promotes the ubiquitination and degradation of mutant HTT (mHTT) in vitro and modulates mHTT aggregation in mouse and monkey brains. Our findings suggest that nonhuman primates are crucial for understanding the mechanisms of human diseases such as HD and support TRIM37 as a potential therapeutic target for treating HD.


Subject(s)
Corpus Striatum , Huntingtin Protein , Huntington Disease , Tripartite Motif Proteins , Ubiquitin-Protein Ligases , Ubiquitination , Huntington Disease/metabolism , Huntington Disease/pathology , Huntington Disease/genetics , Animals , Huntingtin Protein/genetics , Huntingtin Protein/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Tripartite Motif Proteins/metabolism , Tripartite Motif Proteins/genetics , Corpus Striatum/metabolism , Corpus Striatum/pathology , Mice , Humans , Disease Models, Animal , Neurons/metabolism , Neurons/pathology , Proteolysis , Primates
5.
BMC Biol ; 22(1): 121, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38783261

ABSTRACT

BACKGROUND: Huntington disease (HD) is a neurodegenerative disorder with complex motor and behavioural manifestations. The Q175 knock-in mouse model of HD has gained recent popularity as a genetically accurate model of the human disease. However, behavioural phenotypes are often subtle and progress slowly in this model. Here, we have implemented machine-learning algorithms to investigate behaviour in the Q175 model and compare differences between sexes and disease stages. We explore distinct behavioural patterns and motor functions in open field, rotarod, water T-maze, and home cage lever-pulling tasks. RESULTS: In the open field, we observed habituation deficits in two versions of the Q175 model (zQ175dn and Q175FDN, on two different background strains), and using B-SOiD, an advanced machine learning approach, we found altered performance of rearing in male manifest zQ175dn mice. Notably, we found that weight had a considerable effect on performance of accelerating rotarod and water T-maze tasks and controlled for this by normalizing for weight. Manifest zQ175dn mice displayed a deficit in accelerating rotarod (after weight normalization), as well as changes to paw kinematics specific to males. Our water T-maze experiments revealed response learning deficits in manifest zQ175dn mice and reversal learning deficits in premanifest male zQ175dn mice; further analysis using PyMouseTracks software allowed us to characterize new behavioural features in this task, including time at decision point and number of accelerations. In a home cage-based lever-pulling assessment, we found significant learning deficits in male manifest zQ175dn mice. A subset of mice also underwent electrophysiology slice experiments, revealing a reduced spontaneous excitatory event frequency in male manifest zQ175dn mice. CONCLUSIONS: Our study uncovered several behavioural changes in Q175 mice that differed by sex, age, and strain. Our results highlight the impact of weight and experimental protocol on behavioural results, and the utility of machine learning tools to examine behaviour in more detailed ways than was previously possible. Specifically, this work provides the field with an updated overview of behavioural impairments in this model of HD, as well as novel techniques for dissecting behaviour in the open field, accelerating rotarod, and T-maze tasks.


Subject(s)
Behavior, Animal , Body Weight , Disease Models, Animal , Huntington Disease , Phenotype , Animals , Huntington Disease/physiopathology , Huntington Disease/genetics , Mice , Male , Female , Behavior, Animal/physiology , Sex Factors , Age Factors , Machine Learning , Maze Learning
6.
Biomolecules ; 14(5)2024 May 18.
Article in English | MEDLINE | ID: mdl-38786006

ABSTRACT

Age is the primary risk factor for neurodegenerative diseases such as Alzheimer's and Huntington's disease. Alzheimer's disease is the most common form of dementia and a leading cause of death in the elderly population of the United States. No effective treatments for these diseases currently exist. Identifying effective treatments for Alzheimer's, Huntington's, and other neurodegenerative diseases is a major current focus of national scientific resources, and there is a critical need for novel therapeutic strategies. Here, we investigate the potential for targeting the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3HAA) using Caenorhabditis elegans expressing amyloid-beta or a polyglutamine peptide in body wall muscle, modeling the proteotoxicity in Alzheimer's and Huntington's disease, respectively. We show that knocking down the enzyme that degrades 3HAA, 3HAA dioxygenase (HAAO), delays the age-associated paralysis in both models. This effect on paralysis was independent of the protein aggregation in the polyglutamine model. We also show that the mechanism of protection against proteotoxicity from HAAO knockdown is mimicked by 3HAA supplementation, supporting elevated 3HAA as the mediating event linking HAAO knockdown to delayed paralysis. This work demonstrates the potential for 3HAA as a targeted therapeutic in neurodegenerative disease, though the mechanism is yet to be explored.


Subject(s)
3-Hydroxyanthranilic Acid , Amyloid beta-Peptides , Caenorhabditis elegans , Paralysis , Peptides , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/metabolism , Caenorhabditis elegans/genetics , Animals , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/genetics , Peptides/pharmacology , 3-Hydroxyanthranilic Acid/metabolism , Paralysis/chemically induced , Paralysis/metabolism , Paralysis/genetics , Disease Models, Animal , Alzheimer Disease/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/drug therapy , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Huntington Disease/metabolism , Huntington Disease/genetics , Dioxygenases/metabolism , Dioxygenases/genetics
7.
Biochem Biophys Res Commun ; 716: 150010, 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38704892

ABSTRACT

Calcium (Ca2+) in mitochondria plays crucial roles in neurons including modulating metabolic processes. Moreover, excessive Ca2+ in mitochondria can lead to cell death. Thus, altered mitochondrial Ca2+ regulation has been implicated in several neurodegenerative diseases including Huntington's disease (HD). HD is a progressive hereditary neurodegenerative disorder that results from abnormally expanded cytosine-adenine-guanine trinucleotide repeats in the huntingtin gene. One neuropathological hallmark of HD is neuronal loss in the striatum and cortex. However, mechanisms underlying selective loss of striatal and cortical neurons in HD remain elusive. Here, we measured the basal Ca2+ levels and Ca2+ uptake in single presynaptic mitochondria during 100 external electrical stimuli using highly sensitive mitochondria-targeted Ca2+ indicators in cultured cortical and striatal neurons of a knock-in mouse model of HD (zQ175 mice). We observed elevated presynaptic mitochondrial Ca2+ uptake during 100 electrical stimuli in HD cortical neurons compared with wild-type (WT) cortical neurons. We also found the highly elevated presynaptic mitochondrial basal Ca2+ level and Ca2+ uptake during 100 stimuli in HD striatal neurons. The elevated presynaptic mitochondrial basal Ca2+ level in HD striatal neurons and Ca2+ uptake during stimulation in HD striatal and cortical neurons can disrupt neurotransmission and induce mitochondrial Ca2+ overload, eventually leading to neuronal death in the striatum and cortex of HD.


Subject(s)
Calcium , Cerebral Cortex , Corpus Striatum , Disease Models, Animal , Gene Knock-In Techniques , Huntington Disease , Mitochondria , Presynaptic Terminals , Animals , Huntington Disease/metabolism , Huntington Disease/pathology , Huntington Disease/genetics , Calcium/metabolism , Mitochondria/metabolism , Mice , Corpus Striatum/metabolism , Corpus Striatum/pathology , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Presynaptic Terminals/metabolism , Cells, Cultured , Neurons/metabolism , Neurons/pathology , Mice, Transgenic
8.
Cells ; 13(10)2024 May 13.
Article in English | MEDLINE | ID: mdl-38786052

ABSTRACT

Huntington's disease (HD) arises from expanded CAG repeats in exon 1 of the Huntingtin (HTT) gene. The resultant misfolded HTT protein accumulates within neuronal cells, negatively impacting their function and survival. Ultimately, HTT accumulation results in cell death, causing the development of HD. A nonhuman primate (NHP) HD model would provide important insight into disease development and the generation of novel therapies due to their genetic and physiological similarity to humans. For this purpose, we tested CRISPR/Cas9 and a single-stranded DNA (ssDNA) containing expanded CAG repeats in introducing an expanded CAG repeat into the HTT gene in rhesus macaque embryos. Analyses were conducted on arrested embryos and trophectoderm (TE) cells biopsied from blastocysts to assess the insertion of the ssDNA into the HTT gene. Genotyping results demonstrated that 15% of the embryos carried an expanded CAG repeat. The integration of an expanded CAG repeat region was successfully identified in five blastocysts, which were cryopreserved for NHP HD animal production. Some off-target events were observed in biopsies from the cryopreserved blastocysts. NHP embryos were successfully produced, which will help to establish an NHP HD model and, ultimately, may serve as a vital tool for better understanding HD's pathology and developing novel treatments.


Subject(s)
Huntingtin Protein , Macaca mulatta , Animals , Macaca mulatta/genetics , Huntingtin Protein/genetics , Huntingtin Protein/metabolism , Huntington Disease/genetics , Blastocyst/metabolism , Trinucleotide Repeat Expansion/genetics , Embryo, Mammalian/metabolism , CRISPR-Cas Systems/genetics , Female , Disease Models, Animal
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 Biomed Sci ; 31(1): 37, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38627751

ABSTRACT

BACKGROUND: Huntington's disease (HD) is marked by a CAG-repeat expansion in the huntingtin gene that causes neuronal dysfunction and loss, affecting mainly the striatum and the cortex. Alterations in the neurovascular coupling system have been shown to lead to dysregulated energy supply to brain regions in several neurological diseases, including HD, which could potentially trigger the process of neurodegeneration. In particular, it has been observed in cross-sectional human HD studies that vascular alterations are associated to impaired cerebral blood flow (CBF). To assess whether whole-brain changes in CBF are present and follow a pattern of progression, we investigated both resting-state brain perfusion and vascular reactivity longitudinally in the zQ175DN mouse model of HD. METHODS: Using pseudo-continuous arterial spin labelling (pCASL) MRI in the zQ175DN model of HD and age-matched wild-type (WT) mice, we assessed whole-brain, resting-state perfusion at 3, 6 and 9 and 13 months of age, and assessed hypercapnia-induced cerebrovascular reactivity (CVR), at 4.5, 6, 9 and 15 months of age. RESULTS: We found increased perfusion in cortical regions of zQ175DN HET mice at 3 months of age, and a reduction of this anomaly at 6 and 9 months, ages at which behavioural deficits have been reported. On the other hand, under hypercapnia, CBF was reduced in zQ175DN HET mice as compared to the WT: for multiple brain regions at 6 months of age, for only somatosensory and retrosplenial cortices at 9 months of age, and brain-wide by 15 months. CVR impairments in cortical regions, the thalamus and globus pallidus were observed in zQ175DN HET mice at 9 months, with whole brain reactivity diminished at 15 months of age. Interestingly, blood vessel density was increased in the motor cortex at 3 months, while average vessel length was reduced in the lateral portion of the caudate putamen at 6 months of age. CONCLUSION: Our findings reveal early cortical resting-state hyperperfusion and impaired CVR at ages that present motor anomalies in this HD model, suggesting that further characterization of brain perfusion alterations in animal models is warranted as a potential therapeutic target in HD.


Subject(s)
Huntington Disease , Humans , Mice , Animals , Infant , Huntington Disease/genetics , Cross-Sectional Studies , Hypercapnia , Brain , Disease Models, Animal , Perfusion
11.
Proc Natl Acad Sci U S A ; 121(16): e2322924121, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38607933

ABSTRACT

Many Mendelian disorders, such as Huntington's disease (HD) and spinocerebellar ataxias, arise from expansions of CAG trinucleotide repeats. Despite the clear genetic causes, additional genetic factors may influence the rate of those monogenic disorders. Notably, genome-wide association studies discovered somewhat expected modifiers, particularly mismatch repair genes involved in the CAG repeat instability, impacting age at onset of HD. Strikingly, FAN1, previously unrelated to repeat instability, produced the strongest HD modification signals. Diverse FAN1 haplotypes independently modify HD, with rare genetic variants diminishing DNA binding or nuclease activity of the FAN1 protein, hastening HD onset. However, the mechanism behind the frequent and the most significant onset-delaying FAN1 haplotype lacking missense variations has remained elusive. Here, we illustrated that a microRNA acting on 3'-UTR (untranslated region) SNP rs3512, rather than transcriptional regulation, is responsible for the significant FAN1 expression quantitative trait loci signal and allelic imbalance in FAN1 messenger ribonucleic acid (mRNA), accounting for the most significant and frequent onset-delaying modifier haplotype in HD. Specifically, miR-124-3p selectively targets the reference allele at rs3512, diminishing the stability of FAN1 mRNA harboring that allele and consequently reducing its levels. Subsequent validation analyses, including the use of antagomir and 3'-UTR reporter vectors with swapped alleles, confirmed the specificity of miR-124-3p at rs3512. Together, these findings indicate that the alternative allele at rs3512 renders the FAN1 mRNA less susceptible to miR-124-3p-mediated posttranscriptional regulation, resulting in increased FAN1 levels and a subsequent delay in HD onset by mitigating CAG repeat instability.


Subject(s)
Huntington Disease , MicroRNAs , Humans , 3' Untranslated Regions/genetics , Endodeoxyribonucleases , Exodeoxyribonucleases/genetics , Genome-Wide Association Study , Huntington Disease/genetics , MicroRNAs/genetics , Multifunctional Enzymes
12.
Transl Neurodegener ; 13(1): 17, 2024 Apr 02.
Article in English | MEDLINE | ID: mdl-38561866

ABSTRACT

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by aggregation of the mutant huntingtin (mHTT) protein, resulting from a CAG repeat expansion in the huntingtin gene HTT. HD is characterized by a variety of debilitating symptoms including involuntary movements, cognitive impairment, and psychiatric disturbances. Despite considerable efforts, effective disease-modifying treatments for HD remain elusive, necessitating exploration of novel therapeutic approaches, including lifestyle modifications that could delay symptom onset and disease progression. Recent studies suggest that time-restricted eating (TRE), a form of intermittent fasting involving daily caloric intake within a limited time window, may hold promise in the treatment of neurodegenerative diseases, including HD. TRE has been shown to improve mitochondrial function, upregulate autophagy, reduce oxidative stress, regulate the sleep-wake cycle, and enhance cognitive function. In this review, we explore the potential therapeutic role of TRE in HD, focusing on its underlying physiological mechanisms. We discuss how TRE might enhance the clearance of mHTT, recover striatal brain-derived neurotrophic factor levels, improve mitochondrial function and stress-response pathways, and synchronize circadian rhythm activity. Understanding these mechanisms is critical for the development of targeted lifestyle interventions to mitigate HD pathology and improve patient outcomes. While the potential benefits of TRE in HD animal models are encouraging, future comprehensive clinical trials will be necessary to evaluate its safety, feasibility, and efficacy in persons with HD.


Subject(s)
Huntington Disease , Neurodegenerative Diseases , Animals , Humans , Huntington Disease/genetics , Huntington Disease/therapy , Huntington Disease/metabolism , Fasting , Oxidative Stress
13.
Neurobiol Dis ; 195: 106488, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38565397

ABSTRACT

Given their highly polarized morphology and functional singularity, neurons require precise spatial and temporal control of protein synthesis. Alterations in protein translation have been implicated in the development and progression of a wide range of neurological and neurodegenerative disorders, including Huntington's disease (HD). In this study we examined the architecture of polysomes in their native brain context in striatal tissue from the zQ175 knock-in mouse model of HD. We performed 3D electron tomography of high-pressure frozen and freeze-substituted striatal tissue from HD models and corresponding controls at different ages. Electron tomography results revealed progressive remodelling towards a more compacted polysomal architecture in the mouse model, an effect that coincided with the emergence and progression of HD related symptoms. The aberrant polysomal architecture is compatible with ribosome stalling phenomena. In fact, we also detected in the zQ175 model an increase in the striatal expression of the stalling relief factor EIF5A2 and an increase in the accumulation of eIF5A1, eIF5A2 and hypusinated eIF5A1, the active form of eIF5A1. Polysomal sedimentation gradients showed differences in the relative accumulation of 40S ribosomal subunits and in polysomal distribution in striatal samples of the zQ175 model. These findings indicate that changes in the architecture of the protein synthesis machinery may underlie translational alterations associated with HD, opening new avenues for understanding the progression of the disease.


Subject(s)
Disease Models, Animal , Huntington Disease , Polyribosomes , Ribosomes , Animals , Huntington Disease/metabolism , Huntington Disease/pathology , Huntington Disease/genetics , Mice , Polyribosomes/metabolism , Ribosomes/metabolism , Corpus Striatum/metabolism , Corpus Striatum/pathology , Mice, Transgenic , Disease Progression , Huntingtin Protein/genetics , Huntingtin Protein/metabolism , Peptide Initiation Factors/metabolism , Peptide Initiation Factors/genetics
15.
J Neurosci ; 44(20)2024 May 15.
Article in English | MEDLINE | ID: mdl-38589228

ABSTRACT

Protein misfolding, aggregation, and spread through the brain are primary drivers of neurodegenerative disease pathogenesis. Phagocytic glia are responsible for regulating the load of pathological proteins in the brain, but emerging evidence suggests that glia may also act as vectors for aggregate spread. Accumulation of protein aggregates could compromise the ability of glia to eliminate toxic materials from the brain by disrupting efficient degradation in the phagolysosomal system. A better understanding of phagocytic glial cell deficiencies in the disease state could help to identify novel therapeutic targets for multiple neurological disorders. Here, we report that mutant huntingtin (mHTT) aggregates impair glial responsiveness to injury and capacity to degrade neuronal debris in male and female adult Drosophila expressing the gene that causes Huntington's disease (HD). mHTT aggregate formation in neurons impairs engulfment and clearance of injured axons and causes accumulation of phagolysosomes in glia. Neuronal mHTT expression induces upregulation of key innate immunity and phagocytic genes, some of which were found to regulate mHTT aggregate burden in the brain. A forward genetic screen revealed Rab10 as a novel component of Draper-dependent phagocytosis that regulates mHTT aggregate transmission from neurons to glia. These data suggest that glial phagocytic defects enable engulfed mHTT aggregates to evade lysosomal degradation and acquire prion-like characteristics. Together, our findings uncover new mechanisms that enhance our understanding of the beneficial and harmful effects of phagocytic glia in HD and other neurodegenerative diseases.


Subject(s)
Disease Models, Animal , Drosophila Proteins , Drosophila , Huntingtin Protein , Huntington Disease , Neuroglia , Animals , Huntington Disease/metabolism , Huntington Disease/pathology , Huntington Disease/genetics , Neuroglia/metabolism , Neuroglia/pathology , Drosophila Proteins/metabolism , Drosophila Proteins/genetics , Huntingtin Protein/genetics , Huntingtin Protein/metabolism , Female , Male , Phagocytosis/physiology , Lysosomes/metabolism , Phagosomes/metabolism , Animals, Genetically Modified , Prions/metabolism , Prions/genetics , Neurons/metabolism
16.
Clin Neurophysiol ; 162: 121-128, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38603947

ABSTRACT

AIM: The aim of this study was to investigate the characteristics of the electrophysiological brain response elicited in a passive acoustic oddball paradigm, i.e. mismatch negativity (MMN), in patients with Huntington's disease (HD) in the premanifest (pHD) and manifest (mHD) phases. In this regard, we correlated the results of event-related potentials (ERP) with disease characteristics. METHODS: This was an observational cross-sectional MMN study. In addition to the MMN recording of the passive oddball task, all subjects with first-degree inheritance for HD underwent genetic testing for mutant HTT, the Huntington's Disease Rating Scale, the Total Functional Capacity Scale, the Problem Behaviors Assessment short form, and the Mini-Mental State Examination. RESULTS: We found that global field power (GFP) was reduced in the MMN time window in mHD patients compared to pHD and normal controls (NC). In the pHD group, MMN amplitude was only slightly and not significantly increased compared to mHD, while pHD patients showed increased theta coherence between trials compared to mHD. In the entire sample of HD gene carriers, the main MMN traits were not correlated with motor performance, cognitive impairment and functional disability. CONCLUSION: These results suggest an initial and subtle deterioration of pre-attentive mechanisms in the presymptomatic phase of HD, with an increasing phase shift in the MMN time frame. This result could indicate initial functional changes with a possible compensatory effect. SIGNIFICANCE: An initial and slight decrease in MMN associated with increased phase coherence in the corresponding EEG frequencies could indicate an early functional involvement of pre-attentive resources that could precede the clinical expression of HD.


Subject(s)
Huntington Disease , Humans , Huntington Disease/physiopathology , Huntington Disease/genetics , Male , Female , Adult , Middle Aged , Cross-Sectional Studies , Electroencephalography/methods , Evoked Potentials, Auditory/physiology , Acoustic Stimulation/methods , Auditory Perception/physiology , Prodromal Symptoms
17.
Inflammopharmacology ; 32(3): 1791-1804, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38653938

ABSTRACT

Huntington's disease (HD) is an inherited, autosomal, neurodegenerative ailment that affects the striatum of the brain. Despite its debilitating effect on its patients, there is no proven cure for HD management as of yet. Neuroinflammation, excitotoxicity, and environmental factors have been reported to influence the regulation of gene expression by modifying epigenetic mechanisms. Aside focusing on the etiology, changes in epigenetic mechanisms have become a crucial factor influencing the interaction between HTT protein and epigenetically transcribed genes involved in neuroinflammation and HD. This review presents relevant literature on epigenetics with special emphasis on neuroinflammation and HD. It summarizes pertinent research on the role of neuroinflammation and post-translational modifications of chromatin, including DNA methylation, histone modification, and miRNAs. To achieve this about 1500 articles were reviewed via databases like PubMed, ScienceDirect, Google Scholar, and Web of Science. They were reduced to 534 using MeSH words like 'epigenetics, neuroinflammation, and HD' coupled with Boolean operators. Results indicated that major contributing factors to the development of HD such as mitochondrial dysfunction, excitotoxicity, neuroinflammation, and apoptosis are affected by epigenetic alterations. However, the association between neuroinflammation-altered epigenetics and the reported transcriptional changes in HD is unknown. Also, the link between epigenetically dysregulated genomic regions and specific DNA sequences suggests the likelihood that transcription factors, chromatin-remodeling proteins, and enzymes that affect gene expression are all disrupted simultaneously. Hence, therapies that target pathogenic pathways in HD, including neuroinflammation, transcriptional dysregulation, triplet instability, vesicle trafficking dysfunction, and protein degradation, need to be developed.


Subject(s)
Epigenesis, Genetic , Huntington Disease , Neuroinflammatory Diseases , Huntington Disease/genetics , Huntington Disease/therapy , Humans , Animals , Neuroinflammatory Diseases/genetics , DNA Methylation/genetics , Inflammation/genetics
18.
Biochim Biophys Acta Mol Basis Dis ; 1870(1): 166928, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38660915

ABSTRACT

Huntington's disease (HD) is a progressive neurodegenerative disorder with clinical presentations of moderate to severe cognitive, motor, and psychiatric disturbances. HD is caused by the trinucleotide repeat expansion of CAG of the huntingtin (HTT) gene. The mutant HTT protein containing pathological polyglutamine (polyQ) extension is prone to misfolding and aggregation in the brain. It has previously been observed that copper and iron concentrations are increased in the striata of post-mortem human HD brains. Although it has been shown that the accumulation of mutant HTT protein can interact with copper, the underlying HD progressive phenotypes due to copper overload remains elusive. Here, in a Drosophila model of HD, we showed that copper induces dose-dependent aggregational toxicity and enhancement of Htt-induced neurodegeneration. Specifically, we found that copper increases mutant Htt aggregation, enhances the accumulation of Thioflavin S positive ß-amyloid structures within Htt aggregates, and consequently alters autophagy in the brain. Administration of copper chelator D-penicillamine (DPA) through feeding significantly decreases ß-amyloid aggregates in the HD pathological model. These findings reveal a direct role of copper in potentiating mutant Htt protein-induced aggregational toxicity, and further indicate the potential impact of environmental copper exposure in the disease onset and progression of HD.


Subject(s)
Copper , Huntingtin Protein , Huntington Disease , Animals , Humans , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/genetics , Autophagy/drug effects , Autophagy/genetics , Brain/metabolism , Brain/pathology , Brain/drug effects , Copper/metabolism , Copper/toxicity , Disease Models, Animal , Drosophila melanogaster/drug effects , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Huntingtin Protein/genetics , Huntingtin Protein/metabolism , Huntington Disease/genetics , Huntington Disease/metabolism , Huntington Disease/pathology , Mutation , Protein Aggregation, Pathological/genetics , Protein Aggregation, Pathological/metabolism , Protein Aggregation, Pathological/pathology
19.
Stem Cell Res ; 77: 103408, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38569398

ABSTRACT

Neurogenin 2 (NGN2), a neuronal transcription factor, can expedite differentiation of stem cells into mature glutamatergic neurons. We have utilized an allelic series of previously published and characterized isogenic Huntington's disease (IsoHD) human embryonic stem cell lines (Ooi et al., 2019), carrying different CAG repeat lengths in the first exon of the huntingtin gene. These IsoHDs were modified using CRISPR/Cas9 to insert NGN2 under the TET-ON doxycycline inducible promoter. The resulting IsoHD-NGN2 cell lines retained pluripotency in the absence of doxycycline (DOX), and via addition of DOX to the culturing media differentiation to neurons was achieved within 14 days.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors , Doxycycline , Gene Editing , Human Embryonic Stem Cells , Huntington Disease , Nerve Tissue Proteins , Humans , Human Embryonic Stem Cells/metabolism , Human Embryonic Stem Cells/cytology , Huntington Disease/metabolism , Huntington Disease/genetics , Huntington Disease/pathology , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Doxycycline/pharmacology , Cell Line , CRISPR-Cas Systems , Cell Differentiation , Huntingtin Protein/genetics , Huntingtin Protein/metabolism
20.
Rev Neurol (Paris) ; 180(5): 357-362, 2024 May.
Article in English | MEDLINE | ID: mdl-38614929

ABSTRACT

Huntington's disease is a dominantly inherited disorder characterized by the dysfunction and death of cortical and striatal neurons. Striatal degeneration in Huntington's disease is due, at least in part, to defective cortical signalling to the striatum. Although Huntington's disease generally manifests at the adult stage, mouse and neuroimaging studies of presymptomatic mutation carriers suggest that it may affect neurodevelopment. In support of this notion, the development of the cortex is altered in mice with Huntington's disease and the foetuses of human Huntington's disease gene carriers. We will discuss these studies and the contribution of abnormal brain development to the later appearance of the disease.


Subject(s)
Brain , Huntington Disease , Huntington Disease/genetics , Huntington Disease/pathology , Humans , Animals , Mice , Brain/pathology , Brain/diagnostic imaging , Disease Models, Animal , Huntingtin Protein/genetics
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