Identification of a mutant-like conformation of p53 in fibroblasts from sporadic Alzheimer's disease patients

Uberti, Daniela; Lanni, Cristina; Carsana, Teresina; Francisconi, Simona; Missale, Cristina; Racchi, Marco; Govoni, Stefano; Memo, Maurizio

doi:10.1016/j.neurobiolaging.2005.06.013

Cited by 56 publications

(71 citation statements)

References 37 publications

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“…To determine the cell cycle phase distribution of normal human fibroblasts (NHFs) and sAD fibroblasts, flow cyto- 31 Experiments were repeated three times for each sample. To synchronize fibroblasts, cells were seeded at a concentration of 2 ϫ 10 4 cells/cm 2 in a 75-ml flask and grown to 60 to 80% confluence to obtain exponentially growing cells.…”

Section: Flow Cytometric Analysis and Fibroblast Synchronizationmentioning

confidence: 99%

Dynamin-Like Protein 1 Reduction Underlies Mitochondrial Morphology and Distribution Abnormalities in Fibroblasts from Sporadic Alzheimer's Disease Patients

Wang

Fujioka

et al. 2008

The American Journal of Pathology

308

252

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Mitochondrial function relies heavily on its morphology and distribution, alterations of which have been increasingly implicated in neurodegenerative diseases, such as Alzheimer's disease (AD). In this study, we found abnormal mitochondrial distribution characterized by elongated mitochondria that accumulated in perinuclear areas in 19.3% of sporadic AD (sAD) fibroblasts, which was in marked contrast to their normally even cytoplasmic distribution in the majority of human fibroblasts from normal subjects (>95%). Interestingly, levels of dynamin-like protein 1 (DLP1), a regulator of mitochondrial fission and distribution, were decreased significantly in sAD fibroblasts. To explore the potential role of DLP1 in mediating mitochondrial abnormalities in sAD fibroblasts, both the overexpression of a dominant negative DLP1 mutant and the reduced expression of DLP1 by miR RNAi in human fibroblasts from normal subjects significantly increased mitochondrial abnormalities. Moreover, overexpression of wild-type DLP1 in sAD fibroblasts rescued these mitochondrial abnormalities. Based on these data, we conclude that DLP1 reduction causes mitochondrial abnormalities in sAD fibroblasts. We further demonstrate that elevated oxidative stress and increased amyloid ␤ production are likely the potential pathogenic factors that cause DLP1 reduction and abnormal mitochondrial distribution in AD cells. Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles, senile plaques, and progressive loss of neuronal cells in selective brain regions.1 Whereas there are a myriad of striking alterations in the diseased brain, the pathogenesis of the disease is still currently poorly understood. Among these changes, oxidative stress is one of the earliest and may play a critical role in the disease. Mitochondria can be both targets of oxidative damage and sources of reactive oxygen species (ROS), and mitochondrial damage occurs during the aging process, 3 which is associated with memory loss. 4 In fact, damaged mitochondria are less efficient producers of ATP and more efficient producers of ROS. In AD, metabolic abnormalities 5 as well as damage to both the components and the structure of mitochondria are evident. 6 -8 Interestingly, quantitative morphometric studies not only confirm that neurons in AD demonstrate a higher percentage of damaged mitochondria but also reveal enlarged mitochondrial size with decreased mitochondria number in AD neurons. 2,9 The latter finding suggests that the normally strict regulation of mitochondria morphology is impaired, an assertion supported by work showing that AD cybrid cells also contain a significantly increased percentage of enlarged mitochondria. 10Mitochondrial morphology is dynamic and controlled by continual and balanced fission and fusion events that are regulated by a machinery involving large dynaminrelated GTPases that exert opposing effects, eg, dynamin-like protein 1 (DLP1, also referred to as Drp1, DVLP, dymple, HdynIV and DNM1P) [11][12...

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Section: Flow Cytometric Analysis and Fibroblast Synchronizationmentioning

confidence: 99%

Dynamin-Like Protein 1 Reduction Underlies Mitochondrial Morphology and Distribution Abnormalities in Fibroblasts from Sporadic Alzheimer's Disease Patients

Wang

Fujioka

et al. 2008

The American Journal of Pathology

308

252

View full text Add to dashboard Cite

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“…Additionally, fibroblasts from AD patients were more resistant than those from control subjects to H 2 O 2 treatment, although the extent of DNA damage induced by the oxidative injury was similar in both experimental groups. The protective mechanism of AD fibroblasts was related to an impairment of H 2 O 2 -induced cell cycle arrest and characterised by an accelerated re-entry into the cell cycle and a diminished induction of apoptosis which may be due to a profound impairment in the H 2 O 2 -activated, p53-dependent pathway (Uberti et al, 2002;Uberti et al, 2006).…”

Section: +mentioning

confidence: 99%

Skin and brain age together: The role of hormones in the ageing process

Makrantonaki

Schönknecht

Hossini

et al. 2010

Experimental Gerontology

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The importance of the endocrine environment in the initiation of the ageing process has been elucidated in several in vivo an in vitro studies. Changes in endocrine pathways accompany healthy ageing, these include the growth hormone /insulin like growth factor-I axis (somatopause) and that of sexual hormones, namely estradiol (menopause), testosterone (andropause), and dehydroepiandrosterone and its sulphate (adrenopause). The clinical significance of these changes is variable and results in morphological and functional alterations of all organ systems including the skin and the central nervous system. Moreover, the pathogenesis of age-associated diseases such as epithelial skin cancer and neurodegenerative diseases has been partly attributed to the lack of hormones. Several studies have been conducted in an attempt to reverse the ageing process and clinical signs by substitution of the serum hormone levels in older individuals, however the benefits of hormone replacement therapy, if any, are still controversial. On the other hand, recent data suggest that skin is a window to the human organism and represents an adequate model for ageing research, also implying the use of skin samples for evaluating the ageing status of the central nervous system.

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“…The involvement of p53 in neurodegenerative processes has been previously demonstrated following ischemia and different excitotoxic insults [5,19,37]. Post-transcriptional modification can alter p53 tertiary structure and prevent it from binding to specific DNA structures [38].…”

Section: Discussionmentioning

confidence: 94%

Commitment of protein p53 and amyloid-beta peptide (Aβ) in aging of human cerebellum

Maślińska¹,

Laure‐Kamionowska²,

Szukiewicz³

et al. 2017

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Identification of a mutant-like conformation of p53 in fibroblasts from sporadic Alzheimer's disease patients

Cited by 56 publications

References 37 publications

Dynamin-Like Protein 1 Reduction Underlies Mitochondrial Morphology and Distribution Abnormalities in Fibroblasts from Sporadic Alzheimer's Disease Patients

Dynamin-Like Protein 1 Reduction Underlies Mitochondrial Morphology and Distribution Abnormalities in Fibroblasts from Sporadic Alzheimer's Disease Patients

Skin and brain age together: The role of hormones in the ageing process

Commitment of protein p53 and amyloid-beta peptide (Aβ) in aging of human cerebellum

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