A Systematic Review of Transcriptional Dysregulation in Huntington’s Disease Studied by RNA Sequencing

Huntington’s disease (HD) is a chronic neurodegenerative disorder caused by an expansion of polyglutamine repeats in exon 1 of the Huntingtin gene. Transcriptional dysregulation accompanied by epigenetic alterations is an early and central disease mechanism in HD yet, the exact mechanisms and regulators, and their associated gene expression programs remain incompletely understood. This systematic review investigates genome-wide transcriptional studies that were conducted using RNA sequencing (RNA-seq) technology in HD patients and models. The review protocol was registered at the Open Science Framework (OSF). The biomedical literature and gene expression databases, PubMed and NCBI BioProject, Array Express, European Nucleotide Archive (ENA), European Genome-Phenome Archive (EGA), respectively, were searched using the defined terms specified in the protocol following the PRISMA guidelines. We conducted a complete literature and database search to retrieve all RNA-seq-based gene expression studies in HD published until August 2020, retrieving 288 articles and 237 datasets from PubMed and the databases, respectively. A total of 27 studies meeting the eligibility criteria were included in this review. Collectively, comparative analysis of the datasets revealed frequent genes that are consistently dysregulated in HD. In postmortem brains from HD patients, DNAJB1, HSPA1B and HSPB1 genes were commonly upregulated across all brain regions and cell types except for medium spiny neurons (MSNs) at symptomatic disease stage, and HSPH1 and SAT1 genes were altered in expression in all symptomatic brain datasets, indicating early and sustained changes in the expression of genes related to heat shock response as well as response to misfolded proteins. Specifically in indirect pathway medium spiny neurons (iMSNs), mitochondria related genes were among the top uniquely dysregulated genes. Interestingly, blood from HD patients showed commonly differentially expressed genes with a number of brain regions and cells, with the highest number of overlapping genes with MSNs and BA9 region at symptomatic stage. We also found the differential expression and predicted altered activity of a set of transcription factors and epigenetic regulators, including BCL6, EGR1, FOSL2 and CREBBP, HDAC1, KDM4C, respectively, which may underlie the observed transcriptional changes in HD. Altogether, our work provides a complete overview of the transcriptional studies in HD, and by data synthesis, reveals a number of common and unique gene expression and regulatory changes across different cell and tissue types in HD. These changes could elucidate new insights into molecular mechanisms of differential vulnerability in HD.Systematic Review Registration:https://osf.io/pm3wq

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Gene expression profiling of medium spiny neurons in Huntington’s disease model mouse

Journal of the Neurological Sciences ◽

10.1016/j.jns.2017.08.1643 ◽

2017 ◽

Vol 381 ◽

pp. 583

Author(s):

H. Miyazaki ◽

F. Oyama ◽

Y. Kino ◽

M. Kurosawa ◽

M. Yamada-Kurosawa ◽

...

Keyword(s):

Gene Expression ◽

Huntington's Disease ◽

Gene Expression Profiling ◽

Huntington’S Disease ◽

Expression Profiling ◽

Disease Model ◽

Medium Spiny Neurons ◽

Spiny Neurons ◽

Model Mouse

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Striatal Neurodegeneration that Mimics Huntington’s Disease Modifies GABA-induced Currents

Brain Sciences ◽

10.3390/brainsci8120217 ◽

2018 ◽

Vol 8 (12) ◽

pp. 217

Author(s):

Jorge Flores-Hernández ◽

Jeanette Garzón-Vázquez ◽

Gustavo Hernández-Carballo ◽

Elizabeth Nieto-Mendoza ◽

Evelyn Ruíz-Luna ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Gaba Receptors ◽

Gaba Receptor ◽

Receptor Subtype ◽

Medium Spiny Neurons ◽

Nitropropionic Acid ◽

Spiny Neurons ◽

Excitotoxic Damage ◽

Induced Currents

Huntington’s Disease (HD) is a degenerative disease which produces cognitive and motor disturbances. Treatment with GABAergic agonists improves the behavior and activity of mitochondrial complexes in rodents treated with 3-nitropropionic acid to mimic HD symptomatology. Apparently, GABA receptors activity may protect striatal medium spiny neurons (MSNs) from excitotoxic damage. This study evaluates whether mitochondrial inhibition with 3-NP that mimics the early stages of HD, modifies the kinetics and pharmacology of GABA receptors in patch clamp recorded dissociated MSNs cells. The results show that MSNs from mice treated with 3-NP exhibited differences in GABA-induced dose-response currents and pharmacological responses that suggests the presence of GABAC receptors in MSNs. Furthermore, there was a reduction in the effect of the GABAC antagonist that demonstrates a lessening of this GABA receptor subtype activity as a result of mitochondria inhibition.

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BACHD Mice Recapitulate the Striatal Parvalbuminergic Interneuron Loss Found in Huntington’s Disease

Frontiers in Neuroanatomy ◽

10.3389/fnana.2021.673177 ◽

2021 ◽

Vol 15 ◽

Author(s):

Vyshnavi Rallapalle ◽

Annesha C. King ◽

Michelle Gray

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neuronal Population ◽

Medium Spiny Neurons ◽

Cholinergic Interneurons ◽

Spiny Neurons ◽

Parvalbumin Interneurons ◽

Area And Perimeter ◽

Old Mice ◽

Disease Grade

Huntington’s disease (HD) is a dominantly inherited, adult-onset neurodegenerative disease characterized by motor, psychiatric, and cognitive abnormalities. Neurodegeneration is prominently observed in the striatum where GABAergic medium spiny neurons (MSN) are the most affected neuronal population. Interestingly, recent reports of pathological changes in HD patient striatal tissue have identified a significant reduction in the number of parvalbumin-expressing interneurons which becomes more robust in tissues of higher disease grade. Analysis of other interneuron populations, including somatostatin, calretinin, and cholinergic, did not reveal significant neurodegeneration. Electrophysiological experiments in BACHD mice have identified significant changes in the properties of parvalbumin and somatostatin expressing interneurons in the striatum. Furthermore, their interactions with MSNs are altered as the mHTT expressing mouse models age with increased input onto MSNs from striatal somatostatin and parvalbumin-expressing neurons. In order to determine whether BACHD mice recapitulate the alterations in striatal interneuron number as observed in HD patients, we analyzed the number of striatal parvalbumin, somatostatin, calretinin, and choline acetyltransferase positive cells in symptomatic 12–14 month-old mice by immunofluorescent labeling. We observed a significant decrease in the number of parvalbumin-expressing interneurons as well as a decrease in the area and perimeter of these cells. No significant changes were observed for somatostatin, calretinin, or cholinergic interneuron numbers while a significant decrease was observed for the area of cholinergic interneurons. Thus, the BACHD mice recapitulate the degenerative phenotype observed in the parvalbumin interneurons in HD patient striata without affecting the number of other interneuron populations in the striatum.

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A common gene expression signature in Huntington’s disease patient brain regions

BMC Medical Genomics ◽

10.1186/s12920-014-0060-2 ◽

2014 ◽

Vol 7 (1) ◽

Cited By ~ 24

Author(s):

Andreas Neueder ◽

Gillian P Bates

Keyword(s):

Gene Expression ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Patient ◽

Gene Expression Signature ◽

Brain Regions ◽

Common Gene ◽

Expression Signature

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Levodopa-Induced Dyskinesia Is Related to Indirect Pathway Medium Spiny Neuron Excitotoxicity: A Hypothesis Based on an Unexpected Finding

Parkinson s Disease ◽

10.1155/2016/6461907 ◽

2016 ◽

Vol 2016 ◽

pp. 1-5 ◽

Cited By ~ 3

Author(s):

Svetlana A. Ivanova ◽

Anton J. M. Loonen

Keyword(s):

Oxidative Stress ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Age Of Onset ◽

Medium Spiny Neuron ◽

Synaptic Membrane ◽

Medium Spiny Neurons ◽

Unexpected Finding ◽

Indirect Pathway ◽

Spiny Neurons

A serendipitous pharmacogenetic finding links the vulnerability to developing levodopa-induced dyskinesia to the age of onset of Huntington’s disease. Huntington’s disease is caused by a polyglutamate expansion of the protein huntingtin. Aberrant huntingtin is less capable of binding to a member of membrane-associated guanylate kinase family (MAGUKs): postsynaptic density- (PSD-) 95. This leaves more PSD-95 available to stabilize NR2B subunit carrying NMDA receptors in the synaptic membrane. This results in increased excitotoxicity for which particularly striatal medium spiny neurons from the indirect extrapyramidal pathway are sensitive. In Parkinson’s disease the sensitivity for excitotoxicity is related to increased oxidative stress due to genetically determined abnormal metabolism of dopamine or related products. This probably also increases the sensitivity of medium spiny neurons for exogenous levodopa. Particularly the combination of increased oxidative stress due to aberrant dopamine metabolism, increased vulnerability to NMDA induced excitotoxicity, and the particular sensitivity of indirect pathway medium spiny neurons for this excitotoxicity may explain the observed increased prevalence of levodopa-induced dyskinesia.

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Synaptic scaling up in medium spiny neurons of aged BACHD mice: A slow-progression model of Huntington's disease

Neurobiology of Disease ◽

10.1016/j.nbd.2015.10.016 ◽

2016 ◽

Vol 86 ◽

pp. 131-139 ◽

Cited By ~ 16

Author(s):

Anne B. Rocher ◽

Paolo Gubellini ◽

Nicolas Merienne ◽

Lydie Boussicault ◽

Fanny Petit ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Scaling Up ◽

Medium Spiny Neurons ◽

Synaptic Scaling ◽

Progression Model ◽

Spiny Neurons ◽

Slow Progression

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Dysfunction of cAMP-PKA-calcium signaling axis in striatal medium spiny neurons: a role in schizophrenia and Huntington’s disease pathogenesis

10.1101/2021.10.08.463614 ◽

2021 ◽

Author(s):

Marija Fjodorova ◽

Zoe Noakes ◽

Daniel C. De La Fuente ◽

Adam C. Errington ◽

Meng Li

Keyword(s):

Huntington's Disease ◽

Calcium Signaling ◽

Huntington’S Disease ◽

Cortical Neurons ◽

Medium Spiny Neurons ◽

Striatal Neurons ◽

Cell Type ◽

Direct Role ◽

Spiny Neurons ◽

Signaling Axis

SummaryBackgroundStriatal medium spiny neurons (MSNs) are preferentially lost in Huntington’s disease. Genomic studies also implicate a direct role for MSNs in schizophrenia, a psychiatric disorder known to involve cortical neuron dysfunction. It remains unknown whether the two diseases share similar MSN pathogenesis or if neuronal deficits can be attributed to cell type-dependent biological pathways. Transcription factor BCL11B, which is expressed by all MSNs and deep layer cortical neurons, was recently proposed to drive selective neurodegeneration in Huntington’s disease and identified as a candidate risk gene in schizophrenia.MethodsUsing human stem cell-derived neurons lacking BCL11B as a model, we investigated cellular pathology in MSNs and cortical neurons in the context of these disorders. Integrative analyses between differentially expressed transcripts and published GWAS datasets identified cell type-specific disease-related phenotypes.ResultsWe uncover a role for BCL11B in calcium homeostasis in both neuronal types, while deficits in mitochondrial function and protein kinase A (PKA)-dependent calcium transients are detected only in MSNs. Moreover, BCL11B-deficient MSNs display abnormal responses to glutamate and fail to integrate dopaminergic and glutamatergic stimulation, a key feature of striatal neurons in vivo. Gene enrichment analysis reveals overrepresentation of disorder risk genes among BCL11B-regulated pathways, primarily relating to cAMP-PKA-calcium signaling axis and synaptic signaling.ConclusionsOur study indicates that Huntington’s disease and schizophrenia are likely to share neuronal pathogenesis where dysregulation of intracellular calcium levels is found in both striatal and cortical neurons. In contrast, reduction in PKA signaling and abnormal dopamine/glutamate receptor signaling is largely specific to MSNs.

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D08 A Holistic Network Analysis Of Gene Expression Data In Huntington's Disease Patients Reveals A Common Signature Of Transcriptional Dysregulation

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2014-309032.100 ◽

2014 ◽

Vol 85 (Suppl 1) ◽

pp. A34-A34

Author(s):

A. Neueder ◽

G. Bates

Keyword(s):

Gene Expression ◽

Network Analysis ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Gene Expression Data ◽

Expression Data ◽

Transcriptional Dysregulation

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Dysregulated Information Processing by Medium Spiny Neurons in Striatum of Freely Behaving Mouse Models of Huntington's Disease

Journal of Neurophysiology ◽

10.1152/jn.90606.2008 ◽

2008 ◽

Vol 100 (4) ◽

pp. 2205-2216 ◽

Cited By ~ 72

Author(s):

Benjamin R. Miller ◽

Adam G. Walker ◽

Anand S. Shah ◽

Scott J. Barton ◽

George V. Rebec

Keyword(s):

Information Processing ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Mouse Models ◽

Population Level ◽

Medium Spiny Neurons ◽

Processing Scheme ◽

Background Strain ◽

Spiny Neurons ◽

Freely Behaving

Huntington's disease (HD) is an autosomal dominant condition that compromises behavioral output. Dysfunction of medium spiny neurons (MSNs), which are the sole output system of the striatum, is thought to underlie HD pathophysiology. What is not known is how HD alters MSN information processing during behavior, which likely drives the HD behavioral phenotype. We recorded from populations of MSNs in two freely behaving and symptomatic HD mouse models: R6/2 transgenics are based on a C57BL/6J*CBA/J background and show robust behavioral symptoms, whereas knock-in (KI) mice have a 129sv background and express relatively mild behavioral signs. At the single-unit level, we found that the MSN firing rate was elevated in R6/2 but not in KI mice compared with their respective wild-type (WT) controls. In contrast, burst activity, which corresponds to periods of high-frequency firing, was altered in both HD models compared with WT. At the population level, we found that correlated firing between pairs of MSNs was a prominent feature in WT that was reduced in both HD models. Similarly, coincident bursts, which are bursts between pairs of neurons that overlap in time and occur more often in pairs of MSNs that exhibit correlated firing, were decreased in HD mice. Our results indicate an important role in both bursting and correlated burst firing for information processing in MSNs. Dysregulation of this processing scheme, moreover, is a key component of HD pathophysiology regardless of the severity of HD symptoms, genetic construct, and background strain of the mouse models.

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