SMC1A epilepsy syndrome: clinical data from a large international cohort.

SMC1A epilepsy syndrome or developmental and epileptic encephalopathy-85 with or without midline brain defects (DEE85, OMIM #301044) is an X-linked neurologic disorder associated with mutations of the SMC1A gene, which is also responsible for about 5% of patients affected by Cornelia de Lange syndrome spectrum (CdLS). Only described in female patients, SMC1A epilepsy syndrome is characterized by the onset of severe refractory epileptic seizures in the first year of life, global developmental delay, a variable degree of intellectual disability, and dysmorphic facial features not typical of CdLS. This was a descriptive observational study for the largest international cohort with this specific disorder. The main goal of this study was to improve the knowledge of the natural history of this phenotype with particular attention to the psychomotor development and the epilepsy data. The analyzed cohort shows normal prenatal growth with the subsequent development of postnatal microcephaly. The incidence of neonatal problems (seizures and respiratory compromise) is considerable (51.4%). There is a significant prevalence of central nervous system (20%) and cardiovascular malformations (20%). Motor skills are generally delayed. The presence of drug-resistant epilepsy is confirmed; the therapeutic role of a ketogenic diet is still uncertain. The significant regression of previously acquired skills following the onset of seizures has been observed. Facial dysmorphisms are variable and no patient shows a classic CdLS phenotype. To sum up, SMC1A variants caused drug-resistant epilepsy in these patients, more than two-thirds of whom were shown to progress to developmental and epileptic encephalopathy. The SMC1A gene variants are all different from each other (apart from a couple of monozygotic twins), demonstrating the absence of a mutational hotspot in the SMC1A gene. Owing to the absence of phenotypic specificity, whole-exome sequencing is currently the diagnostic gold standard.

Cornelia de Lange Syndrome mutations in SMC1A cause cohesion defects in yeast.

Cornelia de Lange Syndrome (CdLS) is a developmental disorder characterized by limb truncations, craniofacial abnormalities, and cognitive delays. CdLS is caused mainly by mutations in genes encoding subunits or regulators of the cohesin complex. Cohesin plays 2 distinct roles in chromosome dynamics as follows: it promotes looping, organization, and compaction of individual chromosomes, and it holds newly replicated sister chromatids together until cell division. CdLS-associated mutations result in altered gene expression likely by affecting chromosome architecture. Whether CdLS mutations cause phenotypes through impact on sister chromatid cohesion is less clear. Here, we show that CdLS-associated mutations introduced into the SMC1A gene of budding yeast had measurable impacts on sister chromatid cohesion, mitotic progression, and DNA damage sensitivity. These data suggest that sister chromatid cohesion-related defects may contribute to phenotypes seen in CdLS affected individuals.

Case report: The evolving phenotype of ESCO2 spectrum disorder in a 15-year-old Malaysian child.

ESCO2 spectrum disorder is an autosomal recessive developmental disorder characterized by growth retardation, symmetrical mesomelic limb malformation, and distinctive facies with microcephaly, with a wide phenotypic continuum that ranges from Roberts syndrome (MIM #268300) at the severe end to SC phocomelia (MIM #269000) at the milder end. ESCO2 encodes a 601-amino acid protein belonging to the Eco1/Ctf7 family of acetyltransferases that is involved in the establishment of sister chromatid cohesion, which is essential for accurate chromosome segregation and genomic stability and thus belongs to a group of disorders called "cohesinopathies". We describe a 15-year-old Malaysian female who presented with the characteristic triad of ESCO2 spectrum disorder, with an equivocal chromosomal breakage study and normal karyotyping findings. She was initially suspected to have mosaic Fanconi anemia but whole exome sequencing (WES) showed a likely pathogenic homozygous splice variant c.955 + 2_955+5del in the ESCO2 gene. During the 15-year diagnostic odyssey, she developed type 2 diabetes mellitus, primary ovarian insufficiency, increased optic cup-to-disc ratio with tortuous vessels bilaterally, and an evolving but distinct facial and skin hypopigmentation phenotype. Of note, there was an absence of learning disabilities. Our findings provide further evidence for ESCO2 spectrum disorder in an Asian child and contribute to defining the clinical and radiographic spectrum.

Cornelia de Lange Syndrome.

Cornelia de Lange syndrome (CdLS) is a rare, multifactorial, multisystem disorder that affects approximately 1/10,000-100,000 newborns. Mutations and/or variants have been identified in seven genes that have been associated with the diagnosis of this disorder. As all of them affect the cohesin complex, CdLS is also referred to as a "transcriptomopathy" or "cohesinopathy." The phenotype and presentation vary greatly, though there is a classic phenotype that includes a distinctive craniofacial appearance and growth pattern in addition to limb malformations. Because there are multiple overlapping phenotypes with Cornelia de Lange syndrome and other syndromes and sequences, early diagnosis and management of Cornelia de Lange syndrome is imperative. This will enhance the quality of life for individuals with this disorder, as many are now likely to live well into adulthood.

Implications of Dosage Deficiencies in CTCF and Cohesin on Genome Organization, Gene Expression, and Human Neurodevelopment.

Properly organizing DNA within the nucleus is critical to ensure normal downstream nuclear functions. CTCF and cohesin act as major architectural proteins, working in concert to generate thousands of high-intensity chromatin loops. Due to their central role in loop formation, a massive research effort has been dedicated to investigating the mechanism by which CTCF and cohesin create these loops. Recent results lead to questioning the direct impact of CTCF loops on gene expression. Additionally, results of controlled depletion experiments in cell lines has indicated that genome architecture may be somewhat resistant to incomplete deficiencies in CTCF or cohesin. However, heterozygous human genetic deficiencies in CTCF and cohesin have illustrated the importance of their dosage in genome architecture, cellular processes, animal behavior, and disease phenotypes. Thus, the importance of considering CTCF or cohesin levels is especially made clear by these heterozygous germline variants that characterize genetic syndromes, which are increasingly recognized in clinical practice. Defined primarily by developmental delay and intellectual disability, the phenotypes of CTCF and cohesin deficiency illustrate the importance of architectural proteins particularly in neurodevelopment. We discuss the distinct roles of CTCF and cohesin in forming chromatin loops, highlight the major role that dosage of each protein plays in the amplitude of observed effects on gene expression, and contrast these results to heterozygous mutation phenotypes in murine models and clinical patients. Insights highlighted by this comparison have implications for future research into these newly emerging genetic syndromes.

Understanding the new BRD4-related syndrome: Clinical and genomic delineation with an international cohort study.

BRD4 is part of a multiprotein complex involved in loading the cohesin complex onto DNA, a fundamental process required for cohesin-mediated loop extrusion and formation of Topologically Associating Domains. Pathogenic variations in this complex have been associated with a growing number of syndromes, collectively known as cohesinopathies, the most classic being Cornelia de Lange syndrome. However, no cohort study has been conducted to delineate the clinical and molecular spectrum of BRD4-related disorder. We formed an international collaborative study, and collected 14 new patients, including two fetuses. We performed phenotype and genotype analysis, integrated prenatal findings from fetopathological examinations, phenotypes of pediatric patients and adults. We report the first cohort of patients with BRD4-related disorder and delineate the dysmorphic features at different ages. This work extends the phenotypic spectrum of cohesinopathies and characterize a new clinically relevant and recognizable pattern, distinguishable from the other cohesinopathies.

The zebrafish cohesin protein Sgo1 is required for cardiac function and eye development.

BACKGROUND: Cohesinopathies is a term that refers to/covers rare genetic diseases caused by mutations in the cohesin complex proteins. The cohesin complex is a multiprotein complex that facilitates different aspects of cell division, gene transcription, DNA damage repair, and chromosome architecture. Shugoshin proteins prevent the cohesin complex from premature dissociation from chromatids during cell division. Patients with a homozygous missense mutation in SGO1, which encodes for Shugoshin1, have problems with normal pacing of the heart and gut. RESULTS: To study the role of shugoshin during embryo development, we mutated the zebrafish sgo1 gene. Homozygous sgo1 mutant embryos display various phenotypes related to different organs, including a reduced heart rate accompanied by reduced cardiac function. In addition, sgo1 mutants are vision-impaired as a consequence of structurally defective and partially non-functional photoreceptor cells. Furthermore, the sgo1 mutants display reduced food intake and early lethality. CONCLUSION: We have generated a zebrafish model of Sgo1 that showed its importance during organ development and function.

PDS5A and PDS5B in Cohesin Function and Human Disease.

Precocious dissociation of sisters 5 (PDS5) is an associate protein of cohesin that is conserved from yeast to humans. It acts as a regulator of the cohesin complex and plays important roles in various cellular processes, such as sister chromatid cohesion, DNA damage repair, gene transcription, and DNA replication. Vertebrates have two paralogs of PDS5, PDS5A and PDS5B, which have redundant and unique roles in regulating cohesin functions. Herein, we discuss the molecular characteristics and functions of PDS5, as well as the effects of its mutations in the development of diseases and their relevance for novel therapeutic strategies.

Cohesin dysfunction results in cell wall defects in budding yeast.

Cohesin is a conserved chromatin-binding multisubunit protein complex involved in diverse chromosomal transactions such as sister-chromatid cohesion, chromosome condensation, regulation of gene expression, DNA replication, and repair. While working with a budding yeast temperature-sensitive mutant, mcd1-1, defective in a cohesin subunit, we observed that it was resistant to zymolyase, indicating an altered cell wall organization. The budding yeast cell wall is a strong but elastic structure essential for maintenance of cell shape and protection from extreme environmental challenges. Here, we show that the cohesin complex plays an important role in cell wall maintenance. Cohesin mutants showed high chitin content in the cell wall and sensitivity to multiple cell wall stress-inducing agents. Interestingly, temperature-dependent lethality of cohesin mutants was osmoremedial, in a HOG1-MAPK pathway-dependent manner, suggesting that the temperature sensitivity of these mutants may arise partially from cell wall defects. Moreover, Mpk1 hyper-phosphorylation indicated activation of the cell wall integrity (CWI) signaling pathway in cohesin mutants. Genetic interaction analysis revealed that the CWI pathway is essential for survival of mcd1-1 upon additional cell wall stress. The cell wall defect was independent of the cohesion function and accompanied by misregulation of expression of several genes having cell wall-related functions. Our findings reveal a requirement of cohesin in maintenance of CWI that is independent of the CWI pathway, and that may arise from cohesin's role in regulating the expression of multiple genes encoding proteins involved in cell wall organization and biosynthesis.

Essential Roles of Cohesin STAG2 in Mouse Embryonic Development and Adult Tissue Homeostasis.

Cohesin mediates sister chromatid cohesion and 3D genome folding. Two versions of the complex carrying STAG1 or STAG2 coexist in somatic vertebrate cells. STAG2 is commonly mutated in cancer, and germline mutations have been identified in cohesinopathy patients. To better understand the underlying pathogenic mechanisms, we report the consequences of Stag2 ablation in mice. STAG2 is largely dispensable in adults, and its tissue-wide inactivation does not lead to tumors but reduces fitness and affects both hematopoiesis and intestinal homeostasis. STAG2 is also dispensable for murine embryonic fibroblasts in vitro. In contrast, Stag2-null embryos die by mid-gestation and show global developmental delay and defective heart morphogenesis, most prominently in structures derived from secondary heart field progenitors. Both decreased proliferation and altered transcription of tissue-specific genes contribute to these defects. Our results provide compelling evidence on cell- and tissue-specific roles of different cohesin complexes and how their dysfunction contributes to disease.

GSK3-ARC/Arg3.1 and GSK3-Wnt signaling axes trigger amyloid-ß accumulation and neuroinflammation in middle-aged Shugoshin 1 mice.

The cerebral amyloid-ß accumulation that begins in middle age is considered the critical triggering event in the pathogenesis of late-onset Alzheimer's disease (LOAD). However, the molecular mechanism remains elusive. The Shugoshin 1 (Sgo1-/+ ) mouse model, a model for mitotic cohesinopathy-genomic instability that is observed in human AD at a higher rate, showed spontaneous accumulation of amyloid-ß in the brain at old age. With the model, novel insights into the molecular mechanism of LOAD development are anticipated. In this study, the initial appearance of cerebral amyloid-ß accumulation was determined as 15-18 months of age (late middle age) in the Sgo1-/+ model. The amyloid-ß accumulation was associated with unexpected GSK3α/ß inactivation, Wnt signaling activation, and ARC/Arg3.1 accumulation, suggesting involvement of both the GSK3-Arc/Arg3.1 axis and the GSK3-Wnt axis. As observed in human AD brains, neuroinflammation with IFN-γ expression occurred with amyloid-ß accumulation and was pronounced in the aged (24-month-old) Sgo1-/+ model mice. AD-relevant protein panels (oxidative stress defense, mitochondrial energy metabolism, and ß-oxidation and peroxisome) analysis indicated (a) early increases in Pdk1 and Phb in middle-aged Sgo1-/+ brains, and (b) misregulations in 32 proteins among 130 proteins tested in old age. Thus, initial amyloid-ß accumulation in the Sgo1-/+ model is suggested to be triggered by GSK3 inactivation and the resulting Wnt activation and ARC/Arg3.1 accumulation. The model displayed characteristics and affected pathways similar to those of human LOAD including neuroinflammation, demonstrating its potential as a study tool for the LOAD development mechanism and for preclinical AD drug research and development.

MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome.

The NIPBL/MAU2 heterodimer loads cohesin onto chromatin. Mutations in NIPBL account for most cases of the rare developmental disorder Cornelia de Lange syndrome (CdLS). Here we report a MAU2 variant causing CdLS, a deletion of seven amino acids that impairs the interaction between MAU2 and the NIPBL N terminus. Investigating this interaction, we discovered that MAU2 and the NIPBL N terminus are largely dispensable for normal cohesin and NIPBL function in cells with a NIPBL early truncating mutation. Despite a predicted fatal outcome of an out-of-frame single nucleotide duplication in NIPBL, engineered in two different cell lines, alternative translation initiation yields a form of NIPBL missing N-terminal residues. This form cannot interact with MAU2, but binds DNA and mediates cohesin loading. Altogether, our work reveals that cohesin loading can occur independently of functional NIPBL/MAU2 complexes and highlights a novel mechanism protective against out-of-frame mutations that is potentially relevant for other genetic conditions.

A genetic interaction map centered on cohesin reveals auxiliary factors involved in sister chromatid cohesion in S. cerevisiae.

Eukaryotic chromosomes are replicated in interphase and the two newly duplicated sister chromatids are held together by the cohesin complex and several cohesin auxiliary factors. Sister chromatid cohesion is essential for accurate chromosome segregation during mitosis, yet has also been implicated in other processes, including DNA damage repair, transcription and DNA replication. To assess how cohesin and associated factors functionally interconnect and coordinate with other cellular processes, we systematically mapped the genetic interactions of 17 cohesin genes centered on quantitative growth measurements of >52,000 gene pairs in the budding yeast Saccharomyces cerevisiae Integration of synthetic genetic interactions unveiled a cohesin functional map that constitutes 373 genetic interactions, revealing novel functional connections with post-replication repair, microtubule organization and protein folding. Accordingly, we show that the microtubule-associated protein Irc15 and the prefoldin complex members Gim3, Gim4 and Yke2 are new factors involved in sister chromatid cohesion. Our genetic interaction map thus provides a unique resource for further identification and functional interrogation of cohesin proteins. Since mutations in cohesin proteins have been associated with cohesinopathies and cancer, it may also help in identifying cohesin interactions relevant in disease etiology.

"Amyloid-beta accumulation cycle" as a prevention and/or therapy target for Alzheimer's disease.

The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad-spectrum anticancer drugs. Cyclin-dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA-approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid-beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD-omics and preclinical animal models provided data supporting the long-standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re-entry, leading to the "amyloid-beta accumulation cycle," may be a prerequisite for amyloid-beta accumulation and AD pathology development; (b) AD-associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the "amyloid-beta accumulation cycle is an AD drug target" concept is proven, repurposing of cancer drugs may emerge as a new, fast-track approach for AD management in the clinic setting.

Study of carrier frequency of Warsaw breakage syndrome in the Ashkenazi Jewish population and presentation of two cases.

Warsaw breakage syndrome (WABS), caused by bi-allelic variants in the DDX11 gene, is a rare cohesinopathy characterized by pre- and postnatal growth retardation, microcephaly, intellectual disability, facial dysmorphia, and sensorineural hearing loss due to cochlear hypoplasia. The DDX11 gene codes for an iron-sulfur DNA helicase in the Superfamily 2 helicases and plays an important role in genomic stability and maintenance. Fourteen individuals with WABS have been previously reported in the medical literature. Affected individuals have been of various ethnic backgrounds with different pathogenic variants. We report two unrelated individuals of Ashkenazi Jewish descent affected with WABS, who are homozygous for the c.1763-1G>C variant in the DDX11 gene. Their phenotype is consistent with previously reported individuals. RNA studies showed that this variant causes an alternative splice acceptor site leading to a frameshift in the open reading frame. Carrier screening of the c.1763-1G>C variant in the Jewish population revealed a high carrier frequency of 1 in 68 in the Ashkenazi Jewish population. Due to the high carrier frequency and the low number of affected individuals, we hypothesize a high rate of miscarriage of homozygous fetuses and/or subfertility for carrier couples. If the carrier frequency is reproducible in additional Ashkenazi Jewish populations, we suggest including DDX11 to Ashkenazi Jewish carrier screening panels.

A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4 - Review of the literature.

Cornelia de Lange syndrome (CdLS) is a heterogeneous developmental disorder where 70% of clinically diagnosed patients harbor a variant in one of five CdLS associated cohesin proteins. Around 500 variants have been identified to cause CdLS, however only eight different alterations have been identified in the RAD21 gene, encoding the RAD21 cohesin complex component protein that constitute the link between SMC1A and SMC3 within the cohesin ring. We report a 15-month-old boy presenting with developmental delay, distinct CdLS-like facial features, gastrointestinal reflux in early infancy, testis retention, prominent digit pads and diaphragmatic hernia. Exome sequencing revealed a novel RAD21 variant, c.1774_1776del, p.(Gln592del), suggestive of CdLS type 4. Segregation analysis of the two healthy parents confirmed the variant as de novo and bioinformatic analysis predicted the variant as disease-causing. Assessment by in silico structural model predicted that the p.Gln592del variant results in a discontinued contact between RAD21-Lys591 and the SMC1A residues Glu1191 and Glu1192, causing changes in the RAD21-SMC1A interface. In conclusion, we report a patient that expands the clinical description of CdLS type 4 and presents with a novel RAD21 p.(Glu592del) variant that causes a disturbed RAD21-SMC1A interface according to in silco structural modeling.

Roles of cohesin in chromosome architecture and gene expression.

Cohesin-mediated chromatin organization plays an important role in formation and stabilization of chromosome architecture and gene regulation. Mechanisms by which cohesin shapes chromosome and regulates gene expression remain unclear. The present article overviews biological characters and functions of cohesin and core subunits and explores roles of regulatory factors (e.g. Pds5, Wapl, and Eco1) in dynamic behaviors of cohesin. Cohesin interacts with CCCTC binding factor (CTCF) and other factors to maintain and stabilize multi-dimensional organizations of topological loops and distances between sites during cell segmentation. We also describe functional roles of cohesin in cell cycle by entrapping sister chromatids to form embrace and handcuff models, loading onto chromatin, establishing cohesion function, and regulating removal of cohesin and associated factors from the chromosome arm through prophase pathway or at onset of anaphase. It is questioned whether those factors associated with cohesin-regulated processes can be identified as biology- or disease-specific biomarkers and druggable targets to dynamically monitor changes during phasing, staging, progressing, and responding of diseases. It is also expected to explore heterogenetic roles of cohesin between single cells and regulatory roles of cohesin in trans-omic profiles and functions. Further understanding of cohesin functions will be beneficial to improve diagnosis and treatment of cohesinopathies.

Warsaw breakage syndrome: Further clinical and genetic delineation.

Warsaw breakage syndrome (WBS) is a recently recognized DDX11-related rare cohesinopathy, characterized by severe prenatal and postnatal growth restriction, microcephaly, developmental delay, cochlear anomalies, and sensorineural hearing loss. Only seven cases have been reported in the English literature, and thus the information on the phenotype and genotype of this interesting condition is limited. We provide clinical and molecular information on five additional unrelated patients carrying novel bi-allelic variants in the DDX11 gene, identified via whole exome sequencing. One of the variants was found to be a novel Saudi founder variant. All identified variants were classified as pathogenic or likely pathogenic except for one that was initially classified as a variant of unknown significance (VOUS) (p.Arg378Pro). Functional characterization of this VOUS using heterologous expression of wild type and mutant DDX11 revealed a marked effect on protein stability, thus confirming pathogenicity of this variant. The phenotypic data of the seven WBS reported patients were compared to our patients for further phenotypic delineation. Although all the reported patients had cochlear hypoplasia, one patient also had posterior labyrinthine anomaly. We conclude that while the cardinal clinical features in WBS (microcephaly, growth retardation, and cochlear anomalies) are almost universally present, the breakage phenotype is highly variable and can be absent in some cases. This report further expands the knowledge of the phenotypic and molecular features of WBS.

Critical role of mitosis in spontaneous late-onset Alzheimer's disease; from a Shugoshin 1 cohesinopathy mouse model.

From early-onset Alzheimer's disease (EOAD) studies, the amyloid-beta hypothesis emerged as the foremost theory of the pathological causes of AD. However, how amyloid-beta accumulation is triggered and progresses toward senile plaques in spontaneous late-onset Alzheimer's disease (LOAD) in humans remains unanswered. Various LOAD facilitators have been proposed, and LOAD is currently considered a complex disease with multiple causes. Mice do not normally develop LOAD. Possibly due to the multiple causes, proposed LOAD facilitators have not been able to replicate spontaneous LOAD in mice, representing a disease modeling issue. Recently, we reported spontaneous late-onset development of amyloid-beta accumulation in brains of Shugoshin 1 (Sgo1) haploinsufficient mice, a cohesinopathy-mediated chromosome instability model. The result for the first time expands disease relevance of mitosis studies to a major disease other than cancers. Reverse-engineering of the model would shed light on the process of late-onset amyloid-beta accumulation in the brain and spontaneous LOAD development, and contribute to development of interventions for LOAD. This review will discuss the Sgo1 model, our current "three-hit hypothesis" regarding LOAD development with an emphasis on critical role of prolonged mitosis in amyloid-beta accumulation, and implications for human LOAD intervention and treatment. Abbreviations: Alzheimer's disease (AD); Late-onset Alzheimer's disease (LOAD); Early-onset Alzheimer's disease (EOAD); Shugoshin-1 (Sgo1); Chromosome Instability (CIN); apolipoprotein (Apoe); Central nervous system (CNS); Amyloid precursor protein (APP); N-methyl-d-aspartate (NMDA); Hazard ratio (HR); Cyclin-dependent kinase (CDK); Chronic Atrial Intestinal Dysrhythmia (CAID); beta-secretase 1 (BACE); phosphor-Histone H3 (p-H3); Research and development (R&D); Non-steroidal anti-inflammatory drugs (NSAIDs); Brain blood barrier (BBB).

Spontaneous development of Alzheimer's disease-associated brain pathology in a Shugoshin-1 mouse cohesinopathy model.

Spontaneous late-onset Alzheimer's disease (LOAD) accounts for more than 95% of all human AD. As mice do not normally develop AD and as understanding on molecular processes leading to spontaneous LOAD has been insufficient to successfully model LOAD in mouse, no mouse model for LOAD has been available. Existing mouse AD models are all early-onset AD (EOAD) models that rely on forcible expression of AD-associated protein(s), which may not recapitulate prerequisites for spontaneous LOAD. This limitation in AD modeling may contribute to the high failure rate of AD drugs in clinical trials. In this study, we hypothesized that genomic instability facilitates development of LOAD and tested two genomic instability mice models in the brain pathology at the old age. Shugoshin-1 (Sgo1) haploinsufficient (∓) mice, a model of chromosome instability (CIN) with chromosomal and centrosomal cohesinopathy, spontaneously exhibited a major feature of AD pathology; amyloid beta accumulation that colocalized with phosphorylated Tau, beta-secretase 1 (BACE), and mitotic marker phospho-Histone H3 (p-H3) in the brain. Another CIN model, spindle checkpoint-defective BubR1-/+ haploinsufficient mice, did not exhibit the pathology at the same age, suggesting the prolonged mitosis-origin of the AD pathology. RNA-seq identified ten differentially expressed genes, among which seven genes have indicated association with AD pathology or neuronal functions (e.g., ARC, EBF3). Thus, the model represents a novel model that recapitulates spontaneous LOAD pathology in mouse. The Sgo1-/+ mouse may serve as a novel tool for investigating mechanisms of spontaneous progression of LOAD pathology, for early diagnosis markers, and for drug development.