DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic Implication
Emerging studies reveal that neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are commonly linked to DNA damage accumulation and repair deficiency. Neurons are particularly vulnerable to DNA damage due to their high metabolic activity, rel...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-12-01
|
| Series: | Frontiers in Molecular Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2021.784361/full |
| _version_ | 1818361705287122944 |
|---|---|
| author | Haibo Wang Haibo Wang Manohar Kodavati Gavin W. Britz Gavin W. Britz Muralidhar L. Hegde Muralidhar L. Hegde |
| author_facet | Haibo Wang Haibo Wang Manohar Kodavati Gavin W. Britz Gavin W. Britz Muralidhar L. Hegde Muralidhar L. Hegde |
| author_sort | Haibo Wang |
| collection | DOAJ |
| description | Emerging studies reveal that neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are commonly linked to DNA damage accumulation and repair deficiency. Neurons are particularly vulnerable to DNA damage due to their high metabolic activity, relying primarily on oxidative phosphorylation, which leads to increased reactive oxygen species (ROS) generation and subsequent DNA damage. Efficient and timely repair of such damage is critical for guarding the integrity of genomic DNA and for cell survival. Several genes predominantly associated with RNA/DNA metabolism have been implicated in both ALS and FTD, suggesting that the two diseases share a common underlying pathology with varied clinical manifestations. Recent studies reveal that many of the gene products, including RNA/DNA binding proteins (RBPs) TDP-43 and FUS are involved in diverse DNA repair pathways. A key question in the etiology of the ALS/FTD spectrum of neurodegeneration is the mechanisms and pathways involved in genome instability caused by dysfunctions/mutations of those RBP genes and their consequences in the central nervous system. The understanding of such converging molecular mechanisms provides insights into the underlying etiology of the rapidly progressing neurodegeneration in ALS/FTD, while also revealing novel DNA repair target avenues for therapeutic development. In this review, we summarize the common mechanisms of neurodegeneration in ALS and FTD, with a particular emphasis on the DNA repair defects induced by ALS/FTD causative genes. We also highlight the consequences of DNA repair defects in ALS/FTD and the therapeutic potential of DNA damage repair-targeted amelioration of neurodegeneration. |
| first_indexed | 2024-12-13T21:20:56Z |
| format | Article |
| id | doaj.art-6dc8069a270e46cfbfe0827536267e2c |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-13T21:20:56Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-6dc8069a270e46cfbfe0827536267e2c2022-12-21T23:31:06ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992021-12-011410.3389/fnmol.2021.784361784361DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic ImplicationHaibo Wang0Haibo Wang1Manohar Kodavati2Gavin W. Britz3Gavin W. Britz4Muralidhar L. Hegde5Muralidhar L. Hegde6Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, United StatesDepartment of Neuroscience Research at Neurological Surgery, Weill Medical College, New York, NY, United StatesDepartment of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, United StatesDepartment of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, United StatesDepartment of Neuroscience Research at Neurological Surgery, Weill Medical College, New York, NY, United StatesDepartment of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, United StatesDepartment of Neuroscience Research at Neurological Surgery, Weill Medical College, New York, NY, United StatesEmerging studies reveal that neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are commonly linked to DNA damage accumulation and repair deficiency. Neurons are particularly vulnerable to DNA damage due to their high metabolic activity, relying primarily on oxidative phosphorylation, which leads to increased reactive oxygen species (ROS) generation and subsequent DNA damage. Efficient and timely repair of such damage is critical for guarding the integrity of genomic DNA and for cell survival. Several genes predominantly associated with RNA/DNA metabolism have been implicated in both ALS and FTD, suggesting that the two diseases share a common underlying pathology with varied clinical manifestations. Recent studies reveal that many of the gene products, including RNA/DNA binding proteins (RBPs) TDP-43 and FUS are involved in diverse DNA repair pathways. A key question in the etiology of the ALS/FTD spectrum of neurodegeneration is the mechanisms and pathways involved in genome instability caused by dysfunctions/mutations of those RBP genes and their consequences in the central nervous system. The understanding of such converging molecular mechanisms provides insights into the underlying etiology of the rapidly progressing neurodegeneration in ALS/FTD, while also revealing novel DNA repair target avenues for therapeutic development. In this review, we summarize the common mechanisms of neurodegeneration in ALS and FTD, with a particular emphasis on the DNA repair defects induced by ALS/FTD causative genes. We also highlight the consequences of DNA repair defects in ALS/FTD and the therapeutic potential of DNA damage repair-targeted amelioration of neurodegeneration.https://www.frontiersin.org/articles/10.3389/fnmol.2021.784361/fullamyotrophic lateral sclerosisfrontotemporal dementiaFUSDNA damageDNA repair deficiency |
| spellingShingle | Haibo Wang Haibo Wang Manohar Kodavati Gavin W. Britz Gavin W. Britz Muralidhar L. Hegde Muralidhar L. Hegde DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic Implication Frontiers in Molecular Neuroscience amyotrophic lateral sclerosis frontotemporal dementia FUS DNA damage DNA repair deficiency |
| title | DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic Implication |
| title_full | DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic Implication |
| title_fullStr | DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic Implication |
| title_full_unstemmed | DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic Implication |
| title_short | DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic Implication |
| title_sort | dna damage and repair deficiency in als ftd associated neurodegeneration from molecular mechanisms to therapeutic implication |
| topic | amyotrophic lateral sclerosis frontotemporal dementia FUS DNA damage DNA repair deficiency |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2021.784361/full |
| work_keys_str_mv | AT haibowang dnadamageandrepairdeficiencyinalsftdassociatedneurodegenerationfrommolecularmechanismstotherapeuticimplication AT haibowang dnadamageandrepairdeficiencyinalsftdassociatedneurodegenerationfrommolecularmechanismstotherapeuticimplication AT manoharkodavati dnadamageandrepairdeficiencyinalsftdassociatedneurodegenerationfrommolecularmechanismstotherapeuticimplication AT gavinwbritz dnadamageandrepairdeficiencyinalsftdassociatedneurodegenerationfrommolecularmechanismstotherapeuticimplication AT gavinwbritz dnadamageandrepairdeficiencyinalsftdassociatedneurodegenerationfrommolecularmechanismstotherapeuticimplication AT muralidharlhegde dnadamageandrepairdeficiencyinalsftdassociatedneurodegenerationfrommolecularmechanismstotherapeuticimplication AT muralidharlhegde dnadamageandrepairdeficiencyinalsftdassociatedneurodegenerationfrommolecularmechanismstotherapeuticimplication |