Clinicopathological differences between the motor onset and psychiatric onset of Huntington's disease, focusing on the nucleus accumbens

Hirano, Mitsuaki; Iritani, Shuji; Fujishiro, Hiroshige; Torii, Youta; Habuchi, Chikako; Sekiguchi, Hirotaka; Yoshida, Mari; Ozaki, Norio

doi:10.1111/neup.12578

Cited by 8 publications

(11 citation statements)

References 44 publications

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“…With the increased awareness of non-motor aspects of HD, including psychiatric symptoms such as depression, anxiety, apathy, and altered social cognition, as well as metabolic dysfunction with increased appetite, more detailed studies on the ventral striatum have appeared. An early atrophy of the ventral striatum in clinical HD has been found in imaging studies [54], and postmortem human HD studies have identified loss of neurons in this area [55]. The present study shows that the commonly used R6/2 mouse model exhibits ventral neuropathology with a 33% loss of DARPP-32 immunopositive neurons.…”

Section: Discussionsupporting

confidence: 70%

Mutant huntingtin expression in the hypothalamus promotes ventral striatal neuropathology

Soylu-Kucharz

Adlesic

Davidsson

et al. 2023

Preprint

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Huntington’s disease is a fatal neurodegenerative disorder caused by an expanded CAG triplet repeat in the huntingtin (HTT) gene. Previous research focused on neuropathology in the striatum and its association with a typical movement disorder. Direct effects of mutant HTT (mHTT) in the striatum may cause neuropathology, although non-cell autonomous effects have also been suggested. Important non-motor features of HD include psychiatric symptoms and metabolic dysfunction, which may be linked to hypothalamic neuropathology. As hypothalamic neurons project to the ventral striatum, we hypothesized that expression of mHTT in the hypothalamus leads to disrupted neurotransmission in the ventral striatum and causes pathology. The overall aim of this study was to investigate the impact of mHTT expression in the hypothalamus on ventral striatal neuropathology and its contribution to non-HD motor symptoms. We demonstrate that selective expression of mHTT in the hypothalamus leads to the loss of dopamine and cAMP-regulated phosphoprotein (DARPP-32) immunopositive neurons in the ventral striatum in mice. Contrary to the effects of direct expression of mHTT in the hypothalamus, selective overexpression of mHTT in the ventral striatum does not affect body weight. Selective expression of mHTT in the ventral striatum leads to mHTT inclusion formation and loss of DARPP-32 neurons without affecting motor activity or anxiety-like behavior. We show that DARPP-32 neuron loss in the ventral striatum is recapitulated in the R6/2 mouse model of HD. Chemogenetic activation of hypothalamic neurons projecting to the ventral striatum had a blunted response in the R6/2 mice compared to wild-type mice, indicating a disrupted hypothalamus-ventral striatal circuitry. In summary, the expression of mHTT in the hypothalamus may impact the development of ventral striatal pathology in mice. This opens the possibility that non-cell-autonomous effects in the reward circuitry play a role in HD.

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Section: Discussionsupporting

confidence: 70%

Mutant huntingtin expression in the hypothalamus promotes ventral striatal neuropathology

Soylu-Kucharz

Adlesic

Davidsson

et al. 2023

Preprint

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“…The neurodegenerative changes in the cellular structure of the NAc are diversified [ 111 ]. While the changes in the density of small neurons are lesser than in the dorsal striatum, the changes in the density of large neurons are more pronounced.…”

Section: The Nucleus Accumbens Contribution To Neurodegeneration Resu...mentioning

confidence: 99%

“…Moreover, they also depend on the phenotype of the onset of the clinical symptoms. The density of the large neurons in the NAc is increased in patients with neuropsychiatric symptoms compared to patients with the motor symptoms [ 111 ].…”

Section: The Nucleus Accumbens Contribution To Neurodegeneration Resu...mentioning

confidence: 99%

More than Addiction—The Nucleus Accumbens Contribution to Development of Mental Disorders and Neurodegenerative Diseases

Bayassi-Jakowicka

Lietzau

Czuba

et al. 2022

IJMS

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Stress and negative emotions evoked by social relationships and working conditions, frequently accompanied by the consumption of addictive substances, and metabolic and/or genetic predispositions, negatively affect brain function. One of the affected structures is nucleus accumbens (NAc). Although its function is commonly known to be associated with brain reword responses and addiction, a growing body of evidence also suggests its role in some mental disorders, such as depression and schizophrenia, as well as neurodegenerative diseases, such as Alzheimer’s, Huntington’s, and Parkinson’s. This may result from disintegration of the extensive connections based on numerous neurotransmitter systems, as well as impairment of some neuroplasticity mechanisms in the NAc. The consequences of NAc lesions are both morphological and functional. They include changes in the NAc’s volume, cell number, modifications of the neuronal dendritic tree and dendritic spines, and changes in the number of synapses. Alterations in the synaptic plasticity affect the efficiency of synaptic transmission. Modification of the number and structure of the receptors affects signaling pathways, the content of neuromodulators (e.g., BDNF) and transcription factors (e.g., pCREB, DeltaFosB, NFκB), and gene expression. Interestingly, changes in the NAc often have a different character and intensity compared to the changes observed in the other parts of the basal ganglia, in particular the dorsal striatum. In this review, we highlight the role of the NAc in various pathological processes in the context of its structural and functional damage, impaired connections with the other brain areas cooperating within functional systems, and progression of the pathological processes.

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“…Huntington disease (HD) is an incurable neurodegenerative disease characterized by selective loss of specific neuronal populations leading to motor, cognitive and psychiatric impairment 1–7 . Although the disease-causing mutation is present in all brain cells, the severity of the disease varies across brain regions 5, 6 .…”

Section: Introductionmentioning

confidence: 99%

Multi-OMIC analysis of Huntington disease reveals a neuroprotective astrocyte state

Paryani,

Kwon,

et al. 2023

Preprint

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Huntington disease (HD) is an incurable neurodegenerative disease characterized by neuronal loss and astrogliosis. One hallmark of HD is the selective neuronal vulnerability of striatal medium spiny neurons. To date, the underlying mechanisms of this selective vulnerability have not been fully defined. Here, we employed a multi-omic approach including single nucleus RNAseq (snRNAseq), bulk RNAseq, lipidomics,HTTgene CAG repeat length measurements, and multiplexed immunofluorescence on post-mortem brain tissue from multiple brain regions of HD and control donors. We defined a signature of genes that is driven by CAG repeat length and found it enriched in astrocytic and microglial genes. Moreover, weighted gene correlation network analysis showed loss of connectivity of astrocytic and microglial modules in HD and identified modules that correlated with CAG-repeat length which further implicated inflammatory pathways and metabolism. We performed lipidomic analysis of HD and control brains and identified several lipid species that correlate with HD grade, including ceramides and very long chain fatty acids. Integration of lipidomics and bulk transcriptomics identified a consensus gene signature that correlates with HD grade and HD lipidomic abnormalities and implicated the unfolded protein response pathway. Because astrocytes are critical for brain lipid metabolism and play important roles in regulating inflammation, we analyzed our snRNAseq dataset with an emphasis on astrocyte pathology. We found two main astrocyte types that spanned multiple brain regions; these types correspond to protoplasmic astrocytes, and fibrous-like - CD44-positive, astrocytes. HD pathology was differentially associated with these cell types in a region-specific manner. One protoplasmic astrocyte cluster showed high expression of metallothionein genes, the depletion of this cluster positively correlated with the depletion of vulnerable medium spiny neurons in the caudate nucleus. We confirmed that metallothioneins were increased in cingulate HD astrocytes but were unchanged or even decreased in caudate astrocytes. We combined existing genome-wide association studies (GWAS) with a GWA study conducted on HD patients from the original Venezuelan cohort and identified a single-nucleotide polymorphism in the metallothionein gene locus associated with delayed age of onset. Functional studies found that metallothionein overexpressing astrocytes are better able to buffer glutamate and were neuroprotective of patient-derived directly reprogrammed HD MSNs as well as against rotenone-induced neuronal deathin vitro. Finally, we found that metallothionein-overexpressing astrocytes increased the phagocytic activity of microgliain vitroand increased the expression of genes involved in fatty acid binding. Together, we identified an astrocytic phenotype that is regionally-enriched in less vulnerable brain regions that can be leveraged to protect neurons in HD.

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Clinicopathological differences between the motor onset and psychiatric onset of Huntington's disease, focusing on the nucleus accumbens

Cited by 8 publications

References 44 publications

Mutant huntingtin expression in the hypothalamus promotes ventral striatal neuropathology

Mutant huntingtin expression in the hypothalamus promotes ventral striatal neuropathology

More than Addiction—The Nucleus Accumbens Contribution to Development of Mental Disorders and Neurodegenerative Diseases

Multi-OMIC analysis of Huntington disease reveals a neuroprotective astrocyte state

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