Skewed X-Chromosome Inactivation in Women Affected by Alzheimer's Disease

Bajić, Vladan; Mandusic, Vesna; Stefanova, Elka; Božović, Ana; Davidović, Radoslav; Živković, Lada; Čabarkapa, Andrea; Spremo-Potparević, Biljana

doi:10.3233/jad-141674

Cited by 18 publications

(12 citation statements)

References 53 publications

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“…Second, Guam ALS-PDC neurons with tau inclusions also contain mitotic markers [99,100]; such changes result from disruption of neuronal development, as occurs in neonatal rodents treated with cycasin or MAM [1,101,102]. These findings are consistent with emerging evidence indicating that neurons in AD and other tauopathies exhibit binucleation, cell cycle disturbances, and aneuploidy [104][105][106][107][108][109][110]. These findings are consistent with emerging evidence indicating that neurons in AD and other tauopathies exhibit binucleation, cell cycle disturbances, and aneuploidy [104][105][106][107][108][109][110].…”

Section: Occurrence In Cycadssupporting

confidence: 70%

Environmental Neurotoxins Linked to a Prototypical Neurodegenerative Disease

Spencer¹,

Garner²,

Palmer³

et al. 2015

Environmental Factors in Neurodevelopmental and Neurodegenerative Disorders

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Section: Occurrence In Cycadssupporting

confidence: 70%

Environmental Neurotoxins Linked to a Prototypical Neurodegenerative Disease

Spencer¹,

Garner²,

Palmer³

et al. 2015

Environmental Factors in Neurodevelopmental and Neurodegenerative Disorders

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“…Although XCI skewing has been reported in mammalian cells for decades, the mechanisms of the XCI skewing still remain unknown. There are several hypothesized mechanisms that may result in selection against deleterious alleles [27]. For example, a study found that 7.6% of female intellectual disability patients had extreme skewing (> 90:10) to carry mutations of X-linked genes, such as MECP2, DDX3X, and SMC1A, which might result in selection against the cells with mutated genes carried on the active X chromosome [32].…”

Section: Discussionmentioning

confidence: 99%

“…To investigate the relationship between age (age of sampling) and XCI pattern, all SCZ patients and age-matched CNTLs were subgrouped by age as children (age ≤ 18), adults (age [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35], and elderly individuals (age ≥ 50), as shown in Table 1. The MDD patients, who served as psychiatric disease controls for the SCZ patients, were also subgrouped by age as adults (age [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] and elderly individuals (age ≥ 50). The SCZ and MDD patients were diagnosed by at least two experienced psychiatrists according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth or fifth edition (DSM-IV or DSM-V, respectively).…”

Section: Subjectsmentioning

confidence: 99%

A new sex-specific underlying mechanism for female schizophrenia: accelerated skewed X chromosome inactivation

Zhang

et al. 2020

Biol Sex Differ

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Background: X chromosome inactivation (XCI) is the mechanism by which the X-linked gene dosage is adjusted between the sexes. Evidence shows that many sex-specific diseases have their basis in X chromosome biology. While female schizophrenia patients often have a delayed age of disease onset and clinical phenotypes that are different from those of males, it is unknown whether the sex differences in schizophrenia are associated with Xlinked gene dosage and the choice of X chromosome silencing in female cells. Previous studies demonstrated that sex chromosome aneuploidies may be related to the pathogeneses of some psychiatric diseases. Here, we examined the changes in skewed XCI in patients with schizophrenia. Methods: A total of 109 female schizophrenia (SCZ) patients and 80 age-and sex-matched healthy controls (CNTLs) were included in this study. We evaluated clinical features including disease onset age, disease duration, clinical symptoms by the Positive and Negative Syndrome Scale (PANSS) and antipsychotic treatment dosages. The XCI skewing patterns were analyzed by the methylation profile of the HUMARA gene found in DNA isolated from SCZ patient and CNTL leukocytes in the three age groups. Results: First, we found that the frequency of skewed XCI in SCZ patients was 4 times more than that in the ageand sex-matched CNTLs (p < 0.01). Second, we found an earlier onset of severe XCI skewing in the SCZ patients than in CNTLs. Third, we demonstrated a close relationship between the severity of skewed XCI and schizophrenic symptoms (PANSS score ≥ 90) as well as the age of disease onset. Fourth, we demonstrated that the skewed XCI in SCZ patients was not transmitted from the patients' mothers. Limitations: The XCI skewing pattern might differ depending on tissues or organs. Although this is the first study to explore skewed XCI in SCZ, in the future, samples from different tissues or cells in SCZ patients might be important for understanding the impact of skewed XCI in this disease. Conclusion: Our study, for the first time, investigated skewed XCI in female SCZ patients and presented a potential mechanism for the sex differences in SCZ. Our data also suggested that XCI might be a potential target for the development of female-specific interventions for SCZ.

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“…Several authors have suggested that the relatively high frequency of chromosomal alterations was not necessarily related to AD itself, but rather to aging 7,26 . Alzheimer's disease is a systematic disease that accelerates aging.…”

Section: Discussionmentioning

confidence: 99%

Investigation of chromosomal alterations in patients with Alzheimer's disease in the state of Amazonas, Brazil

Nunes

Benzaquem

Carvalho

et al. 2019

Arq. Neuro-Psiquiatr.

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Alzheimer's disease (AD) has as its main characteristic the deterioration of cerebral functions. Its etiology is still complex and undefined despite the progress made in understanding its neurological, infectious, biochemical, genetic and cytogenetic mechanisms. Considering this, the aim of this study was to investigate the presence of chromosomal alterations in the peripheral blood lymphocytes, and to verify if there was a high frequency of these alterations in patients diagnosed with AD at the University Hospital GetúLio Vargas Outpatient Clinic Araújo Lima in Manaus, Amazonas, Brazil. Among the nine patients in the AD group, only one patient did not have metaphases with chromosomal alterations (2n = 46,XX), while eight patients with AD showed numerical chromosomal alterations, classified as X chromosome aneupLoidy (2n = 45,X) and double aneupLoidy (2n = 44,X,-X,-10; 2n = 44,X,-X,-13 and 2n = 44,X,-X,-21). In the control group, no chromosomal changes were found in the karyotypes of these individuals. Therefore, the karyotypes of patients with AD undergo chromosomal alterations at different levels. These findings are being described for the first time in the population of Amazonas, and they highlight the importance of the inclusion of cytogenetic investigations in the routine management of patients with AD.

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Skewed X-Chromosome Inactivation in Women Affected by Alzheimer's Disease

Cited by 18 publications

References 53 publications

Environmental Neurotoxins Linked to a Prototypical Neurodegenerative Disease

Environmental Neurotoxins Linked to a Prototypical Neurodegenerative Disease

A new sex-specific underlying mechanism for female schizophrenia: accelerated skewed X chromosome inactivation

Investigation of chromosomal alterations in patients with Alzheimer's disease in the state of Amazonas, Brazil

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