Human dermal fibroblasts in psychiatry research

Kálmán, Sára; Garbett, Krassimira A.; Janka, Zoltán; Mirnics, Károly

doi:10.1016/j.neuroscience.2016.01.067

Cited by 29 publications

(32 citation statements)

References 216 publications

(211 reference statements)

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“…A number of different cell types have been used to assess the effects of small molecules on Chol biosynthesis. While we have successfully used Dhcr7-deficient and WT Neuro2a cells (17,21,31) in the past for screening purposes, human patient-derived dermal fibroblasts represent an ideal model for follow-up experiments (32). As a result, for the purpose of assessing the effect of small molecule DHCR7 inhibitors on a cell having only one allele bearing a DHCR7 mutation, we chose human fibroblasts (HFs) from six DHCR7 +/ HET parents of a SLOS offspring and six age-and sex-matched donors from a CTR population.…”

Section: Dhcr7 Genetic Variantsmentioning

confidence: 99%

Vulnerability of DHCR7+/− mutation carriers to aripiprazole and trazodone exposure

Korade

Genaro-Mattos

Tallman

et al. 2017

Journal of Lipid Research

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Smith-Lemli-Opitz syndrome is a recessive disorder caused by mutations in 7-dehydrocholesterol reductase (DHCR)7 with a heterozygous (HET) carrier frequency of 1-3%. A defective DHCR7 causes accumulation of 7-dehydrocholesterol (DHC), which is a highly oxidizable and toxic compound. Recent studies suggest that several antipsychotics, including the highly prescribed pharmaceuticals, aripiprazole (ARI) and trazodone (TRZ), increase 7-DHC levels in vitro and in humans. Our investigation was designed to compare the effects of ARI and TRZ on cholesterol (Chol) synthesis in fibroblasts from human carriers and controls (CTRs). Six matched pairs of fibroblasts were treated and their sterol profile analyzed by LC-MS. Significantly, upon treatment with ARI and TRZ, the total accumulation of 7-DHC was higher in-HET cells than in CTR fibroblasts. The same set of experiments was repeated in the presence of C-lanosterol to determine residual Chol synthesis, revealing that ARI and TRZ strongly inhibit de novo Chol biosynthesis. The results suggest that carriers have increased vulnerability to both ARI and TRZ exposure compared with CTRs. Thus, the 1-3% of the population who are DHCR7 carriers may be more likely to sustain deleterious health consequences on exposure to compounds like ARI and TRZ that increase levels of 7-DHC, especially during brain development.

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Section: Dhcr7 Genetic Variantsmentioning

confidence: 99%

Vulnerability of DHCR7+/− mutation carriers to aripiprazole and trazodone exposure

Korade

Genaro-Mattos

Tallman

et al. 2017

Journal of Lipid Research

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“…Several groups had suggested the use of peripheral tissues as a reliable source of biomarkers that could reflex the metabolic changes in the brain (Yao et al, 2011 ; Perez et al, 2016 ). In fact, there are several examples of using skin fibroblasts to study metabolic abnormalities related to neurological (Zoumakis et al, 2007 ), psychiatric (Kalman et al, 2016 ), neurometabolic (Khan and Alkon, 2015 ) and neurodegenerative diseases (Lopez-Erauskin et al, 2012 ; Ambrosi et al, 2014 ), in particular Huntington's disease (Marchina et al, 2014 ), Parkinson's disease (Rakovic et al, 2010 ; Cooper et al, 2012 ; Papkovskaia et al, 2012 ; Mcneill et al, 2013 ), and genetic forms of Amyotrophic Lateral Sclerosis (Bartolome et al, 2013 ; Prause et al, 2013 ; Allen et al, 2014 ). For that reason, it has been suggested that biochemical changes in brain cells could be reflected in peripheral tissues derived from ectoderm, such as skin (Zoumakis et al, 2007 ), and that this tissue represents a suitable model to study potential new biomarkers in AD and other neurodegenerative diseases (Khan and Alkon, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Bioenergetics Is Altered in Fibroblasts from Patients with Sporadic Alzheimer's Disease

et al. 2017

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The identification of an early biomarker to diagnose Alzheimer's disease (AD) remains a challenge. Neuropathological studies in animal and AD patients have shown that mitochondrial dysfunction is a hallmark of the development of the disease. Current studies suggest the use of peripheral tissues, like skin fibroblasts as a possibility to detect the early pathological alterations present in the AD brain. In this context, we studied mitochondrial function properties (bioenergetics and morphology) in cultured fibroblasts obtained from AD, aged-match and young healthy patients. We observed that AD fibroblasts presented a significant reduction in mitochondrial length with important changes in the expression of proteins that control mitochondrial fusion. Moreover, AD fibroblasts showed a distinct alteration in proteolytic processing of OPA1, a master regulator of mitochondrial fusion, compared to control fibroblasts. Complementary to these changes AD fibroblasts showed a dysfunctional mitochondrial bioenergetics profile that differentiates these cells from aged-matched and young patient fibroblasts. Our findings suggest that the human skin fibroblasts obtained from AD patients could replicate mitochondrial impairment observed in the AD brain. These promising observations suggest that the analysis of mitochondrial bioenergetics could represent a promising strategy to develop new diagnostic methods in peripheral tissues of AD patients.

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“…These findings are very relevant because several publications suggest that the basic pathogenic mechanism of amyloidogenesis is similar in brain and skin fibroblasts, with an increase in the production and depositions of Aβ [128,142]. Therefore, a mitochondrial deregulation in the fibroblasts of AD patients could be indicative of the neurological progression of the disease [143,144].…”

Section: Evidence For Mitochondrial Dynamics Defects In Ad Peripheralmentioning

confidence: 80%

New Targets for Diagnosis and Treatment Against Alzheimer’s Disease: The Mitochondrial Approach

Pérez¹,

Jara²,

Muñoz‐Urrutia³

et al. 2016

Update on Dementia

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Alzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia. AD is characterized by brain presence of senile plaques, which are formed by aggregates of Aβ peptide and neurofibrillary tangles (NFTs), formed by pathological forms of tau protein. Evidence suggests that these elements affect neurons compromising energy supply, antioxidant response and synaptic activity. AD principally affects the memory and cognitive functions of the patients, and currently, successful strategies for diagnosis and early treatment are lacking. In this scenario, accumulative evidence suggests that mitochondrial dysfunction precedes the establishment of tau and Aβ pathology and contributes to synaptic degeneration observed in AD. Therefore, reducing mitochondrial injury may have beneficial effects for neuronal dysfunction and cognitive decline observed in AD patients. Interestingly, the examination of peripheral cells from AD patients also presents mitochondrial dysfunction, suggesting that tracking these mitochondrial defects in peripheral cells could be a potential mechanism of early diagnosis of AD. In this chapter, we analyse current evidence that suggests that mitochondrial injury is an important factor in the pathogenesis of AD and how studying this process could reveal new strategies to mitigate neurodegeneration and to develop new diagnostic methods for an early detection of AD.

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Human dermal fibroblasts in psychiatry research

Cited by 29 publications

References 216 publications

Vulnerability of DHCR7+/− mutation carriers to aripiprazole and trazodone exposure

Vulnerability of DHCR7+/− mutation carriers to aripiprazole and trazodone exposure

Mitochondrial Bioenergetics Is Altered in Fibroblasts from Patients with Sporadic Alzheimer's Disease

New Targets for Diagnosis and Treatment Against Alzheimer’s Disease: The Mitochondrial Approach

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