The pleiotropic role of p53 in functional/dysfunctional neurons: focus on pathogenesis and diagnosis of Alzheimer’s disease
Abstract Background Understanding the earliest pathophysiological changes of Alzheimer’s disease (AD) may aid in the search for timely diagnostic biomarkers and effective disease-modifying therapies. The p53 protein is mostly known for its role in tumor suppression. However, emerging evidence suppor...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-12-01
|
| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13195-020-00732-0 |
| _version_ | 1818384422764806144 |
|---|---|
| author | Giulia Abate Giovanni B. Frisoni Jean-Christophe Bourdon Simona Piccirella Maurizio Memo Daniela Uberti |
| author_facet | Giulia Abate Giovanni B. Frisoni Jean-Christophe Bourdon Simona Piccirella Maurizio Memo Daniela Uberti |
| author_sort | Giulia Abate |
| collection | DOAJ |
| description | Abstract Background Understanding the earliest pathophysiological changes of Alzheimer’s disease (AD) may aid in the search for timely diagnostic biomarkers and effective disease-modifying therapies. The p53 protein is mostly known for its role in tumor suppression. However, emerging evidence supports that dysregulated p53 activity may contribute to various peripheral and brain alterations during the earliest stages of AD. This review describes the mechanisms through which p53 dysregulation may exacerbate AD pathology and how this could be used as a potential peripheral biomarker for early detection of the disease. Main body p53, known as the guardian of the genome, may underlie various compensation or defense mechanisms that prevent neurons from degeneration. These mechanisms include maintenance of redox homeostasis, regulation of inflammation, control of synaptic function, reduction of amyloid β peptides, and inhibition of neuronal cell cycle re-entry. Thereby, dysregulation of p53-dependent compensation mechanisms may contribute to neuronal dysfunction, thus leading to neurodegeneration. Interestingly, a conformational misfolded variant of p53, described in the literature as unfolded p53, which has lost its canonical structure and function, was observed in peripheral cells from mild cognitive impairment (MCI) and AD patients. In AD pathology, this peculiar conformational variant was caused by post-translational modifications rather than mutations as commonly observed in cancer. Although the presence of the conformational variant of p53 in the brain has yet to be formally demonstrated, the plethora of p53-dependent compensation mechanisms underscores that the guardian of the genome may not only be lost in the periphery during AD pathology. Conclusion These findings revisit the role of p53 in the early development and exacerbation of AD pathology, both in the brain and periphery. The conformational variant of p53 represents a potential peripheral biomarker that could detect AD at its earliest stages. |
| first_indexed | 2024-12-14T03:22:01Z |
| format | Article |
| id | doaj.art-52c04e8da51346f2b4cfd93f388345d4 |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-12-14T03:22:01Z |
| publishDate | 2020-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-52c04e8da51346f2b4cfd93f388345d42022-12-21T23:19:01ZengBMCAlzheimer’s Research & Therapy1758-91932020-12-0112111010.1186/s13195-020-00732-0The pleiotropic role of p53 in functional/dysfunctional neurons: focus on pathogenesis and diagnosis of Alzheimer’s diseaseGiulia Abate0Giovanni B. Frisoni1Jean-Christophe Bourdon2Simona Piccirella3Maurizio Memo4Daniela Uberti5Department of Molecular and Translational Medicine, University of BresciaMemory Clinic, University Hospitals and University of GenevaSchool of Medicine, University of DundeeDiadem srlDepartment of Molecular and Translational Medicine, University of BresciaDepartment of Molecular and Translational Medicine, University of BresciaAbstract Background Understanding the earliest pathophysiological changes of Alzheimer’s disease (AD) may aid in the search for timely diagnostic biomarkers and effective disease-modifying therapies. The p53 protein is mostly known for its role in tumor suppression. However, emerging evidence supports that dysregulated p53 activity may contribute to various peripheral and brain alterations during the earliest stages of AD. This review describes the mechanisms through which p53 dysregulation may exacerbate AD pathology and how this could be used as a potential peripheral biomarker for early detection of the disease. Main body p53, known as the guardian of the genome, may underlie various compensation or defense mechanisms that prevent neurons from degeneration. These mechanisms include maintenance of redox homeostasis, regulation of inflammation, control of synaptic function, reduction of amyloid β peptides, and inhibition of neuronal cell cycle re-entry. Thereby, dysregulation of p53-dependent compensation mechanisms may contribute to neuronal dysfunction, thus leading to neurodegeneration. Interestingly, a conformational misfolded variant of p53, described in the literature as unfolded p53, which has lost its canonical structure and function, was observed in peripheral cells from mild cognitive impairment (MCI) and AD patients. In AD pathology, this peculiar conformational variant was caused by post-translational modifications rather than mutations as commonly observed in cancer. Although the presence of the conformational variant of p53 in the brain has yet to be formally demonstrated, the plethora of p53-dependent compensation mechanisms underscores that the guardian of the genome may not only be lost in the periphery during AD pathology. Conclusion These findings revisit the role of p53 in the early development and exacerbation of AD pathology, both in the brain and periphery. The conformational variant of p53 represents a potential peripheral biomarker that could detect AD at its earliest stages.https://doi.org/10.1186/s13195-020-00732-0Alzheimer’s diseasep53Conformational variant of p53 |
| spellingShingle | Giulia Abate Giovanni B. Frisoni Jean-Christophe Bourdon Simona Piccirella Maurizio Memo Daniela Uberti The pleiotropic role of p53 in functional/dysfunctional neurons: focus on pathogenesis and diagnosis of Alzheimer’s disease Alzheimer’s Research & Therapy Alzheimer’s disease p53 Conformational variant of p53 |
| title | The pleiotropic role of p53 in functional/dysfunctional neurons: focus on pathogenesis and diagnosis of Alzheimer’s disease |
| title_full | The pleiotropic role of p53 in functional/dysfunctional neurons: focus on pathogenesis and diagnosis of Alzheimer’s disease |
| title_fullStr | The pleiotropic role of p53 in functional/dysfunctional neurons: focus on pathogenesis and diagnosis of Alzheimer’s disease |
| title_full_unstemmed | The pleiotropic role of p53 in functional/dysfunctional neurons: focus on pathogenesis and diagnosis of Alzheimer’s disease |
| title_short | The pleiotropic role of p53 in functional/dysfunctional neurons: focus on pathogenesis and diagnosis of Alzheimer’s disease |
| title_sort | pleiotropic role of p53 in functional dysfunctional neurons focus on pathogenesis and diagnosis of alzheimer s disease |
| topic | Alzheimer’s disease p53 Conformational variant of p53 |
| url | https://doi.org/10.1186/s13195-020-00732-0 |
| work_keys_str_mv | AT giuliaabate thepleiotropicroleofp53infunctionaldysfunctionalneuronsfocusonpathogenesisanddiagnosisofalzheimersdisease AT giovannibfrisoni thepleiotropicroleofp53infunctionaldysfunctionalneuronsfocusonpathogenesisanddiagnosisofalzheimersdisease AT jeanchristophebourdon thepleiotropicroleofp53infunctionaldysfunctionalneuronsfocusonpathogenesisanddiagnosisofalzheimersdisease AT simonapiccirella thepleiotropicroleofp53infunctionaldysfunctionalneuronsfocusonpathogenesisanddiagnosisofalzheimersdisease AT mauriziomemo thepleiotropicroleofp53infunctionaldysfunctionalneuronsfocusonpathogenesisanddiagnosisofalzheimersdisease AT danielauberti thepleiotropicroleofp53infunctionaldysfunctionalneuronsfocusonpathogenesisanddiagnosisofalzheimersdisease AT giuliaabate pleiotropicroleofp53infunctionaldysfunctionalneuronsfocusonpathogenesisanddiagnosisofalzheimersdisease AT giovannibfrisoni pleiotropicroleofp53infunctionaldysfunctionalneuronsfocusonpathogenesisanddiagnosisofalzheimersdisease AT jeanchristophebourdon pleiotropicroleofp53infunctionaldysfunctionalneuronsfocusonpathogenesisanddiagnosisofalzheimersdisease AT simonapiccirella pleiotropicroleofp53infunctionaldysfunctionalneuronsfocusonpathogenesisanddiagnosisofalzheimersdisease AT mauriziomemo pleiotropicroleofp53infunctionaldysfunctionalneuronsfocusonpathogenesisanddiagnosisofalzheimersdisease AT danielauberti pleiotropicroleofp53infunctionaldysfunctionalneuronsfocusonpathogenesisanddiagnosisofalzheimersdisease |