CAG Trinucleotide Repeat Expansion Research Articles

Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington's Disease.

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. We report the design of a series of HTT pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of HTT mRNA transcripts and protein levels. The starting benzamide core was modified to pyrazine amide and further optimized to give a potent, CNS-penetrant, and orally bioavailable HTT-splicing modulator 27. This compound reduced canonical splicing of the HTT RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound 27 is a structurally diverse HTT-splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam.

Understanding Polyglutamine Diseases and Investigating the Functions of HSP90 and RPL36

The expansion of CAG trinucleotide repeats has been considered to be highly related to the polyglutamine disorders which effect the neuron and muscle system of organism. This study aims to investigate how knocking down HSP90 or RPL36 would affect the polyglutamine toxicity. Based on the previous experiment, the Caenorhabditis elegans that expresses polyQ proteins would show protein misfolding and aggregation. We use C. elegans as model and record the phenotype of worms, frequency of thrashing and number of aggregations under IHA microscope before and after close the target genes by RNA interference. The results of this experiment indicate that HSP90 deficiency increases polyglutamine toxicity in muscle cells, presumably by preventing polyglutamine protein aggregation. Otherwise, rpl36 knockdown suppresses polyglutamine toxicity in muscle cells, perhaps by stimulating the aggregation of polyglutamine proteins. The research work has contributed to our present understanding to polyglutamine disorder and the possible function of HSP90 and RPL36.

Transcriptional and Histone Acetylation Changes Associated with CRE Elements Expose Key Factors Governing the Regulatory Circuit in the Early Stage of Huntington's Disease Models.

Huntington's disease (HD) is a disorder caused by an abnormal expansion of trinucleotide CAG repeats within the huntingtin (Htt) gene. Under normal conditions, the CREB Binding Protein interacts with CREB elements and acetylates Lysine 27 of Histone 3 to direct the expression of several genes. However, mutant Htt causes depletion of CBP, which in turn induces altered histone acetylation patterns and transcriptional deregulation. Here, we have studied a differential expression analysis and H3K27ac variation in 4- and 6-week-old R6/2 mice as a model of juvenile HD. The analysis of differential gene expression and acetylation levels were integrated into Gene Regulatory Networks revealing key regulators involved in the altered transcription cascade. Our results show changes in acetylation and gene expression levels that are related to impaired neuronal development, and key regulators clearly defined in 6-week-old mice are proposed to drive the downstream regulatory cascade in HD. Here, we describe the first approach to determine the relationship among epigenetic changes in the early stages of HD. We determined the existence of changes in pre-symptomatic stages of HD as a starting point for early onset indicators of the progression of this disease.

Loss of TDP-43 promotes somatic CAG repeat expansion in Huntington’s disease knock-in mice

TAR binding protein 43 (TDP-43) is normally present in the nucleus but mislocalized in the cytoplasm in a number of neurodegenerative diseases including Huntington’s disease (HD). The nuclear loss of TDP-43 impairs gene transcription and regulation. However, it remains to be investigated whether loss of TDP-43 influences trinucleotide CAG repeat expansion in the HD gene, a genetic cause for HD. Here we report that CRISPR/Cas9 mediated-knock down of endogenous TDP-43 in the striatum of HD knock-in mice promoted CAG repeat expansion, accompanied by the increased expression of the DNA mismatch repair genes, Msh3 and Mlh1, which have been reported to increase trinucleotide repeat instability. Furthermore, suppressing Msh3 and Mlh1 by CRISPR/Cas9 targeting diminished the CAG repeat expansion. These findings suggest that nuclear TDP-43 deficiency may dysregulate the expression of DNA mismatch repair genes, leading to CAG repeat expansion and contributing to the pathogenesis of CAG repeat diseases.

Toxicity of copper and zinc alone and in combination in Caenorhabditis elegans model of Huntington's disease and protective effects of rutin

Copper (Cu) and Zinc (Zn) are required in small concentrations for metabolic functions, but are also toxic. There is a great concern about soil pollution by heavy metals, which may exposure the population to these toxicants, either by inhalation of dust or exposure to toxicants through ingestion of food derived from contaminated soils. In addition, the toxicity of metals in combination is questionable, as soil quality guidelines only assess them separately. It is well known that metal accumulation is often found in the pathologically affected regions of many neurodegenerative diseases, including Huntington's disease (HD). HD is caused by an autosomal dominantly inherited CAG trinucleotide repeat expansion in the huntingtin (HTT) gene. This results in the formation of a mutant huntingtin (mHTT) protein with an abnormally long polyglutamine (polyQ) repeat. The pathology of HD results in loss of neuronal cells, motor changes, and dementia. Rutin is a flavonoid found in various food sources, and previous studies indicate it has protective effects in HD models and acts as a metal chelator. However, further studies are needed to unravel its effects on metal dyshomeostasis and to discern the underlying mechanisms. In the present study, we investigated the toxic effects of long-term exposure to copper, zinc, and their mixture, and the relationship with the progression of neurotoxicity and neurodegeneration in a C. elegans-based HD model. Furthermore, we investigated the effects of rutin post metal exposure. Overall, we demonstrate that chronic exposure to the metals and their mixture altered body parameters, locomotion, and developmental delay, in addition to increasing polyQ protein aggregates in muscles and neurons causing neurodegeneration. We also propose that rutin has protective effects acting through mechanisms involving antioxidant and chelating properties. Altogether, our data provides new indications about the higher toxicity of metals in combination, the chelating potential of rutin in the C. elegans model of HD and possible strategies for future treatments of neurodegenerative diseases caused by the aggregation of proteins related to metals.

Elevated levels of mosaic aneuploidy in brain cells and fibroblast cell lines from human Huntington’s disease donors and in brain cells from Huntington’s disease mouse models

AbstractBackgroundHuntington’s disease (HD) is a progressive neurodegenerative disorder that presents with motor and cognitive deficits and psychiatric disturbances. HD is associated with autosomal dominant inheritance of a CAG trinucleotide repeat expansion mutation in the huntingtin (HTT) gene. The huntingtin protein localizes to spindle poles and is required for proper mitotic spindle orientation, chromosome segregation, and cell cycle regulation. The mature mutant huntingtin protein has an expanded polyglutamine region (>35 repeats) near its N terminus, which leads to neuronal dysfunction and death. Mouse models of HD exhibit defects in microtubule function and cell cycle regulation. Studies from our laboratory and others have shown elevated levels of aneuploidy in many neurodegenerative disorders characterized by cognitive deficits, including Alzheimer’s disease and frontotemporal lobar degeneration. Here, we investigated whether chromosome segregation defects that lead to mosaic aneuploidy and consequent apoptosis may also contribute to neuronal loss in HD.MethodsSingle‐cell suspensions from cortex and cerebellum from human HD donors were analyzed using FISH for chromosome 21, NeuN immunostaining, and/or TUNEL staining. Fibroblast cell lines from human HD donors were also analyzed using FISH. Single‐cell suspensions from cortex and cerebellum from HD mouse models were analyzed using FISH for chromosomes 5 and 16. Cell cycle arrest, mitotic spindle defects, ploidy, and apoptosis profiles in the HD fibroblast cell lines are being analyzed by flow cytometry and immunofluorescence microscopy.ResultsIncreased levels of mosaic aneuploidy and apoptosis were observed in brain cells and in fibroblast cell lines from HD donors compared to age‐matched healthy control donors. Increased levels of mosaic aneuploidy were also observed in brain cells from HD mice compared to age‐matched wild‐type control mice. Results of ongoing studies of cell cycle and mitotic defects will also be presented.ConclusionsTaken together with the results of our previous studies, these data provide evidence that chromosome segregation defects that lead to genomic instability may serve as a shared mechanism underlying many neurodegenerative disorders. Our findings highlight the need to further investigate the biological mechanism(s) that contribute to HD pathology and set the stage for novel therapeutic approaches to HD that may also be applied to other neurodegenerative disorders.

What the Gut Tells the Brain—Is There a Link between Microbiota and Huntington’s Disease?

The human intestinal microbiota is a diverse and dynamic microenvironment that forms a complex, bi-directional relationship with the host. The microbiome takes part in the digestion of food and the generation of crucial nutrients such as short chain fatty acids (SCFA), but is also impacts the host's metabolism, immune system, and even brain functions. Due to its indispensable role, microbiota has been implicated in both the maintenance of health and the pathogenesis of many diseases. Dysbiosis in the gut microbiota has already been implicated in many neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). However, not much is known about the microbiome composition and its interactions in Huntington's disease (HD). This dominantly heritable, incurable neurodegenerative disease is caused by the expansion of CAG trinucleotide repeats in the huntingtin gene (HTT). As a result, toxic RNA and mutant protein (mHTT), rich in polyglutamine (polyQ), accumulate particularly in the brain, leading to its impaired functions. Interestingly, recent studies indicated that mHTT is also widely expressed in the intestines and could possibly interact with the microbiota, affecting the progression of HD. Several studies have aimed so far to screen the microbiota composition in mouse models of HD and find out whether observed microbiome dysbiosis could affect the functions of the HD brain. This review summarizes ongoing research in the HD field and highlights the essential role of the intestine-brain axis in HD pathogenesis and progression. The review also puts a strong emphasis on indicating microbiome composition as a future target in the urgently needed therapy for this still incurable disease.

Repeat-associated non-AUG translation induces cytoplasmic aggregation of CAG repeat-containing RNAs

CAG trinucleotide repeat expansions cause several neurodegenerative diseases, including Huntington's disease and spinocerebellar ataxia. RNAs with expanded CAG repeats contribute to disease in two unusual ways. First, these repeat-containing RNAs may agglomerate in the nucleus as foci that sequester several RNA-binding proteins. Second, these RNAs may undergo aberrant repeat-associated non-AUG (RAN) translation in multiple frames and produce aggregation-prone proteins. The relationship between RAN translation and RNA foci, and their relative contributions to cellular dysfunction, are unclear. Here, we show that CAG repeat-containing RNAs that undergo RAN translation first accumulate at nuclear foci and, over time, are exported to the cytoplasm. In the cytoplasm, these RNAs are initially dispersed but, upon RAN translation, aggregate with the RAN translation products. These RNA-RAN protein agglomerates sequester various RNA-binding proteins and are associated with the disruption of nucleocytoplasmic transport and cell death. In contrast, RNA accumulation at nuclear foci alone does not produce discernable defects in nucleocytoplasmic transport or cell viability. Inhibition of RAN translation prevents cytoplasmic RNA aggregation and alleviates cell toxicity. Our findings demonstrate that RAN translation-induced RNA-protein aggregation correlates with the key pathological hallmarks observed in disease and suggest that cytoplasmic RNA aggregation may be an underappreciated phenomenon in CAG trinucleotide repeat expansion disorders.

Renin-angiotensin system in the central nervous system: focus on Huntington's disease.

Renin-angiotensin system in the central nervous system: focus on Huntington's disease.

Huntingtin Decreases Susceptibility to a Spontaneous Seizure Disorder in FVN/B Mice.

Huntington disease (HD) is an adult-onset neurodegenerative disorder that is caused by a trinucleotide CAG repeat expansion in the HTT gene that codes for the protein huntingtin (HTT in humans or Htt in mice). HTT is a multi-functional, ubiquitously expressed protein that is essential for embryonic survival, normal neurodevelopment, and adult brain function. The ability of wild-type HTT to protect neurons against various forms of death raises the possibility that loss of normal HTT function may worsen disease progression in HD. Huntingtin-lowering therapeutics are being evaluated in clinical trials for HD, but concerns have been raised that decreasing wild-type HTT levels may have adverse effects. Here we show that Htt levels modulate the occurrence of an idiopathic seizure disorder that spontaneously occurs in approximately 28% of FVB/N mice, which we have called FVB/N Seizure Disorder with SUDEP (FSDS). These abnormal FVB/N mice demonstrate the cardinal features of mouse models of epilepsy including spontaneous seizures, astrocytosis, neuronal hypertrophy, upregulation of brain-derived neurotrophic factor (BDNF), and sudden seizure-related death. Interestingly, mice heterozygous for the targeted inactivation of Htt (Htt+/- mice) exhibit an increased frequency of this disorder (71% FSDS phenotype), while over-expression of either full length wild-type HTT in YAC18 mice or full length mutant HTT in YAC128 mice completely prevents it (0% FSDS phenotype). Examination of the mechanism underlying huntingtin's ability to modulate the frequency of this seizure disorder indicated that over-expression of full length HTT can promote neuronal survival following seizures. Overall, our results demonstrate a protective role for huntingtin in this form of epilepsy and provide a plausible explanation for the observation of seizures in the juvenile form of HD, Lopes-Maciel-Rodan syndrome, and Wolf-Hirschhorn syndrome. Adverse effects caused by decreasing huntingtin levels have ramifications for huntingtin-lowering therapies that are being developed to treat HD.

Reduction in PA28αβ activation in HD mouse brain correlates to increased mHTT aggregation in cell models.

Huntington's disease is an autosomal dominant heritable disorder caused by an expanded CAG trinucleotide repeat at the N-terminus of the Huntingtin (HTT) gene. Lowering the levels of soluble mutant HTT protein prior to aggregation through increased degradation by the proteasome would be a therapeutic strategy to prevent or delay the onset of disease. Native PAGE experiments in HdhQ150 mice and R6/2 mice showed that PA28αβ disassembles from the 20S proteasome during disease progression in the affected cortex, striatum and hippocampus but not in cerebellum and brainstem. Modulating PA28αβ activated proteasomes in various in vitro models showed that PA28αβ improved polyQ degradation, but decreased the turnover of mutant HTT. Silencing of PA28αβ in cells lead to an increase in mutant HTT aggregates, suggesting that PA28αβ is critical for overall proteostasis, but only indirectly affects mutant HTT aggregation.

De novo emergence, existence, and demise of a protein-coding gene in murids.

Genes, principal units of genetic information, vary in complexity and evolutionary history. Less-complex genes (e.g., long non-coding RNA (lncRNA) expressing genes) readily emerge de novo from non-genic sequences and have high evolutionary turnover. Genesis of a gene may be facilitated by adoption of functional genic sequences from retrotransposon insertions. However, protein-coding sequences in extant genomes rarely lack any connection to an ancestral protein-coding sequence. We describe remarkable evolution of the murine gene D6Ertd527e and its orthologs in the rodent Muroidea superfamily. The D6Ertd527e emerged in a common ancestor of mice and hamsters most likely as a lncRNA-expressing gene. A major contributing factor was a long terminal repeat (LTR) retrotransposon insertion carrying an oocyte-specific promoter and a 5' terminal exon of the gene. The gene survived as an oocyte-specific lncRNA in several extant rodents while in some others the gene or its expression were lost. In the ancestral lineage of Mus musculus, the gene acquired protein-coding capacity where the bulk of the coding sequence formed through CAG (AGC) trinucleotide repeat expansion and duplications. These events generated a cytoplasmic serine-rich maternal protein. Knock-out of D6Ertd527e in mice has a small but detectable effect on fertility and the maternal transcriptome. While this evolving gene is not showing a clear function in laboratory mice, its documented evolutionary history in Muroidea during the last ~ 40 million years provides a textbook example of how a several common mutation events can support de novo gene formation, evolution of protein-coding capacity, as well as gene's demise.

Haplotyping SNPs for allele-specific gene editing of the expanded huntingtin allele using long-read sequencing.

SummaryHuntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by CAG trinucleotide repeat expansions in exon-1 of huntingtin (HTT). Currently, there is no cure for HD, and the clinical care of individuals with HD is focused on symptom management. Previously, we showed allele-specific deletion of the expanded HTT allele (mHTT) using CRISPR-Cas9 by targeting nearby (<10 kb) SNPs that created or eliminated a protospacer adjacent motif (PAM) near exon-1. Here, we comprehensively analyzed all potential PAM sites within a 10.4-kb genomic region flanking exon-1 of HTT in 983 individuals with HD using a multiplex targeted long-read sequencing approach on the Oxford Nanopore platform. We developed computational tools (NanoBinner and NanoRepeat) to de-multiplex the data, detect repeats, and phase the reads on the expanded or the wild-type HTT allele. One SNP common to 30% of individuals with HD of European ancestry emerged through this analysis, which was confirmed as a strong candidate for allele-specific deletion of the mHTT in human HD cell lines. In addition, up to 57% HD individuals may be candidates for allele-specific editing through combinatorial SNP targeting. Cumulatively, we provide a haplotype map of the region surrounding exon-1 of HTT in individuals affected with HD. Our workflow can be applied to other repeat expansion diseases to facilitate the design of guide RNAs for allele-specific gene editing.

Emerging Therapies for Huntington's Disease - Focus on N-Terminal Huntingtin and Huntingtin Exon 1.

Huntington’s disease is a devastating heritable neurodegenerative disorder that is caused by the presence of a trinucleotide CAG repeat expansion in the Huntingtin gene, leading to a polyglutamine tract in the protein. Various mechanisms lead to the production of N-terminal Huntingtin protein fragments, which are reportedly more toxic than the full-length protein. In this review, we summarize the current knowledge on the production and toxicity of N-terminal Huntingtin protein fragments. Further, we expand on various therapeutic strategies targeting N-terminal Huntingtin on the protein, RNA and DNA level. Finally, we compare the therapeutic approaches that are clinically most advanced, including those that do not target N-terminal Huntingtin, discussing differences in mode of action and translational applicability.

Huntington's Disease: A Clinical Review.

The Huntington's gene on chromosome 4 has a dominantly inherited CAG trinucleotide repeat expansion, ultimately resulting in Huntington's disease (HD), a completely penetrant neurological condition. The frequency is 10-100 times higher in the population descended from Europe than in East Asia. Through various processes, including impairment of proteostasis, transcription, and cell function, as well as direct toxicity of the mutant protein, mutated huntingtin triggers neuronal malfunction and loss at the cellular level. As the disease worsens, the brain becomes affected together with the striatum's initial macroscopic alterations. Since there are presently few medications that can change the course of the disease, palliative therapy, and symptom control are the cornerstone of treatment. Studying the cellular pathology and gross structural changes to the brain which occur as the illness advances have made enormous progress in recent years. There's been a substantial increase in medical studies and possible treatment options over the past ten years. The new treatments that aim to reduce amounts of mutant huntingtin are the most optimistic. However, one strategy is antisense oligonucleotide treatment, for which clinical trials are currently being conducted. These control trials might help us get another inch ahead of managing and perhaps even eliminating this nasty disease.

Protein Kinase CK2 and Its Potential Role as a Therapeutic Target in Huntington's Disease.

Huntington’s Disease (HD) is a devastating neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene, for which no disease modifying therapies are currently available. Much of the recent research has focused on developing therapies to directly lower HTT expression, and while promising, these therapies have presented several challenges regarding administration and efficacy. Another promising therapeutic approach is the modulation of HTT post-translational modifications (PTMs) that are dysregulated in disease and have shown to play a key role in HTT toxicity. Among all PTMs, modulation of HTT phosphorylation has been proposed as an attractive therapeutic option due to the possibility of orally administering specific kinase effectors. One of the kinases described to participate in HTT phosphorylation is Protein Kinase CK2. CK2 has recently emerged as a target for the treatment of several neurological and psychiatric disorders, although its role in HD remains controversial. While pharmacological studies in vitro inhibiting CK2 resulted in reduced HTT phosphorylation and increased toxicity, genetic approaches in mouse models of HD have provided beneficial effects. In this review we discuss potential therapeutic approaches related to the manipulation of HTT-PTMs with special emphasis on the role of CK2 as a therapeutic target in HD.

CAG Repeat Instability in the Peripheral and Central Nervous System of Transgenic Huntington's Disease Monkeys.

Huntington’s Disease (HD) is an autosomal dominant disease that results in severe neurodegeneration with no cure. HD is caused by the expanded CAG trinucleotide repeat (TNR) on the Huntingtin gene (HTT). Although the somatic and germline expansion of the CAG repeats has been well-documented, the underlying mechanisms had not been fully delineated. Increased CAG repeat length is associated with a more severe phenotype, greater TNR instability, and earlier age of onset. The direct relationship between CAG repeat length and molecular pathogenesis makes TNR instability a useful measure of symptom severity and tissue susceptibility. Thus, we examined the tissue-specific TNR instability of transgenic nonhuman primate models of Huntington’s disease. Our data show a similar profile of CAG repeat expansion in both rHD1 and rHD7, where high instability was observed in testis, liver, caudate, and putamen. CAG repeat expansion was observed in all tissue samples, and tissue- and CAG repeat size-dependent expansion was observed. Correlation analysis of CAG repeat expansion and the gene expression profile of four genes in different tissues, clusterin (CLU), transferrin (TF), ribosomal protein lateral stalk subunit P1 (RPLP1), and ribosomal protein L13a (RPL13A), showed a strong correlation with CAG repeat instability. Overall, our data, along with previously published studies, can be used for studying the biology of CAG repeat instability and identifying new therapeutic targets.

Derivation of spinocerebellar ataxia type 3 human embryonic stem cell line UMICHe001-A/UM134-1

The most common autosomal dominant ataxia worldwide, spinocerebellar ataxia type 3 (SCA3) is a fatal, progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the ATXN3 gene. Here we report the generation of human embryonic stem cell (hESC) line UM134-1, the first SCA3 disease-specific hESC line to be added to the NIH hESC registry. UM134-1 pluripotency was confirmed by immunocytochemistry and PCR for pluripotency markers and by the ability to form three germ layers in vitro. The established hESC line provides a useful new human cell model to study the pathogenesis of SCA3.

Synaptic and functional alterations in the development of mutant huntingtin expressing hiPSC-derived neurons.

Huntington’s disease (HD) is a monogenic disease that results in a combination of motor, psychiatric, and cognitive symptoms. It is caused by a CAG trinucleotide repeat expansion in the exon 1 of the huntingtin (HTT) gene, which results in the production of a mutant HTT protein (mHTT) with an extended polyglutamine tract (PolyQ). Severe motor symptoms are a hallmark of HD and typically appear during middle age; however, mild cognitive and personality changes often occur already during early adolescence. Wild-type HTT is a regulator of synaptic functions and plays a role in axon guidance, neurotransmitter release, and synaptic vesicle trafficking. These functions are important for proper synapse assembly during neuronal network formation. In the present study, we assessed the effect of mHTT exon1 isoform on the synaptic and functional maturation of human induced pluripotent stem cell (hiPSC)-derived neurons. We used a relatively fast-maturing hiPSC line carrying a doxycycline-inducible pro-neuronal transcription factor, (iNGN2), and generated a double transgenic line by introducing only the exon 1 of HTT, which carries the mutant CAG (mHTTEx1). The characterization of our cell lines revealed that the presence of mHTTEx1 in hiPSC-derived neurons alters the synaptic protein appearance, decreases synaptic contacts, and causes a delay in the development of a mature neuronal activity pattern, recapitulating some of the developmental alterations observed in HD models, nonetheless in a shorted time window. Our data support the notion that HD has a neurodevelopmental component and is not solely a degenerative disease.

CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in huntington’s disease

Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene for which no therapies are available. HTT mutation causes protein misfolding and aggregation, preferentially affecting medium spiny neurons (MSNs) of the basal ganglia. Transcriptional perturbations in synaptic genes and neuroinflammation are key processes that precede MSN dysfunction and motor symptom onset. Understanding the interplay between these processes is crucial to develop effective therapeutic strategies to treat HD. We investigated the role of protein kinase CK2α’, a kinase upregulated in MSNs in HD and previously associated with Parkinson’s disease (PD), in the regulation of neuroinflammation and synaptic function in HD. We used the heterozygous knock-in zQ175 HD mouse model and compared that to zQ175 mice lacking one allele of CK2α’ (zQ175:CK2α’(±)). CK2α’ haploinsufficiency in zQ175 mice resulted in decreased levels of pro-inflammatory cytokines, HTT aggregation, astrogliosis and transcriptional alterations of synaptic genes related to glutamatergic signaling. zQ175:CK2α’(±) mice also presented increased frequency of striatal miniature excitatory postsynaptic currents (mEPSCs), an indicator of synaptic activity, and improved motor coordination compared to zQ175 mice. Neuropathological and phenotypic changes mediated by CK2α’ were connected to alpha-synuclein (α-syn) dysregulation and correlated with differences in α-syn serine 129 phosphorylation (pS129-α-syn), a post-translational modification involved in α-synucleinopathy and shown to be regulated by CK2 in PD. pS129-α-syn was increased in the nuclei of MSNs in zQ175 mice and in the striatum of patients with HD, and it decreased in zQ175:CK2α’(±) mice. Collectively, our data established a novel connection between CK2α’, neuroinflammation and synaptic gene dysregulation with synucleinopathy in HD and suggested common molecular mechanisms of neurodegeneration between HD and PD. Our results also support CK2α’ inhibition as a potential therapeutic strategy to modulate neuronal function and neuroprotection in HD.