Neonatal Brain Injury and Genetic Causes of Adult-Onset Neurodegenerative Disease in Mice Interact With Effects on Acute and Late Outcomes
Neonatal brain damage and age-related neurodegenerative disease share many common mechanisms of injury involving mitochondriopathy, oxidative stress, excitotoxicity, inflammation, and neuronal cell death. We hypothesized that genes causing adult-onset neurodegeneration can influence acute outcome af...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-06-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fneur.2019.00635/full |
| _version_ | 1818875925716008960 |
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| author | Lee J. Martin Lee J. Martin Lee J. Martin Margaret Wong Allison Hanaford |
| author_facet | Lee J. Martin Lee J. Martin Lee J. Martin Margaret Wong Allison Hanaford |
| author_sort | Lee J. Martin |
| collection | DOAJ |
| description | Neonatal brain damage and age-related neurodegenerative disease share many common mechanisms of injury involving mitochondriopathy, oxidative stress, excitotoxicity, inflammation, and neuronal cell death. We hypothesized that genes causing adult-onset neurodegeneration can influence acute outcome after CNS injury at immaturity and on the subsequent development of chronic disability after early-life brain injury. In two different transgenic (Tg) mouse models of adult-onset neurodegenerative disease, a human A53T-α-synuclein (hαSyn) model of Parkinson's disease (PD) and a human G93A-superoxide dismutase-1(hSOD1) model of amyotrophic lateral sclerosis (ALS), mortality and survivor morbidity were significantly greater than non-Tg mice and a Tg mouse model of Alzheimer's disease after neonatal traumatic brain injury (TBI). Acutely after brain injury, hαSyn neonatal mice showed a marked enhancement of protein oxidative damage in forebrain, brain regional mitochondrial oxidative metabolism, and mitochondriopathy. Extreme protein oxidative damage was also observed in neonatal mutant SOD1 mice after TBI. At 1 month of age, neuropathology in forebrain, midbrain, and brainstem of hαSyn mice with neonatal TBI was greater compared to sham hαSyn mice. Surviving hαSyn mice with TBI showed increased hαSyn aggregation and nitration and developed adult-onset disease months sooner and died earlier than non-injured hαSyn mice. Surviving hSOD1 mice with TBI also developed adult-onset disease and died sooner than non-injured hSOD1 mice. We conclude that mutant genes causing PD and ALS in humans have significant impact on mortality and morbidity after early-life brain injury and on age-related disease onset and proteinopathy in mice. This study provides novel insight into genetic determinants of poor outcomes after acute injury to the neonatal brain and how early-life brain injury can influence adult-onset neurodegenerative disease during aging. |
| first_indexed | 2024-12-19T13:34:15Z |
| format | Article |
| id | doaj.art-8fe28a86b3204449a160f2849fc13a6c |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-12-19T13:34:15Z |
| publishDate | 2019-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-8fe28a86b3204449a160f2849fc13a6c2022-12-21T20:19:15ZengFrontiers Media S.A.Frontiers in Neurology1664-22952019-06-011010.3389/fneur.2019.00635442012Neonatal Brain Injury and Genetic Causes of Adult-Onset Neurodegenerative Disease in Mice Interact With Effects on Acute and Late OutcomesLee J. Martin0Lee J. Martin1Lee J. Martin2Margaret Wong3Allison Hanaford4Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesPathobiology Graduate Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDivision of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesPathobiology Graduate Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesNeonatal brain damage and age-related neurodegenerative disease share many common mechanisms of injury involving mitochondriopathy, oxidative stress, excitotoxicity, inflammation, and neuronal cell death. We hypothesized that genes causing adult-onset neurodegeneration can influence acute outcome after CNS injury at immaturity and on the subsequent development of chronic disability after early-life brain injury. In two different transgenic (Tg) mouse models of adult-onset neurodegenerative disease, a human A53T-α-synuclein (hαSyn) model of Parkinson's disease (PD) and a human G93A-superoxide dismutase-1(hSOD1) model of amyotrophic lateral sclerosis (ALS), mortality and survivor morbidity were significantly greater than non-Tg mice and a Tg mouse model of Alzheimer's disease after neonatal traumatic brain injury (TBI). Acutely after brain injury, hαSyn neonatal mice showed a marked enhancement of protein oxidative damage in forebrain, brain regional mitochondrial oxidative metabolism, and mitochondriopathy. Extreme protein oxidative damage was also observed in neonatal mutant SOD1 mice after TBI. At 1 month of age, neuropathology in forebrain, midbrain, and brainstem of hαSyn mice with neonatal TBI was greater compared to sham hαSyn mice. Surviving hαSyn mice with TBI showed increased hαSyn aggregation and nitration and developed adult-onset disease months sooner and died earlier than non-injured hαSyn mice. Surviving hSOD1 mice with TBI also developed adult-onset disease and died sooner than non-injured hSOD1 mice. We conclude that mutant genes causing PD and ALS in humans have significant impact on mortality and morbidity after early-life brain injury and on age-related disease onset and proteinopathy in mice. This study provides novel insight into genetic determinants of poor outcomes after acute injury to the neonatal brain and how early-life brain injury can influence adult-onset neurodegenerative disease during aging.https://www.frontiersin.org/article/10.3389/fneur.2019.00635/fullneonatal brain damagetraumatic brain injuryALSsynuclein oligomerizationParkinson's disease |
| spellingShingle | Lee J. Martin Lee J. Martin Lee J. Martin Margaret Wong Allison Hanaford Neonatal Brain Injury and Genetic Causes of Adult-Onset Neurodegenerative Disease in Mice Interact With Effects on Acute and Late Outcomes Frontiers in Neurology neonatal brain damage traumatic brain injury ALS synuclein oligomerization Parkinson's disease |
| title | Neonatal Brain Injury and Genetic Causes of Adult-Onset Neurodegenerative Disease in Mice Interact With Effects on Acute and Late Outcomes |
| title_full | Neonatal Brain Injury and Genetic Causes of Adult-Onset Neurodegenerative Disease in Mice Interact With Effects on Acute and Late Outcomes |
| title_fullStr | Neonatal Brain Injury and Genetic Causes of Adult-Onset Neurodegenerative Disease in Mice Interact With Effects on Acute and Late Outcomes |
| title_full_unstemmed | Neonatal Brain Injury and Genetic Causes of Adult-Onset Neurodegenerative Disease in Mice Interact With Effects on Acute and Late Outcomes |
| title_short | Neonatal Brain Injury and Genetic Causes of Adult-Onset Neurodegenerative Disease in Mice Interact With Effects on Acute and Late Outcomes |
| title_sort | neonatal brain injury and genetic causes of adult onset neurodegenerative disease in mice interact with effects on acute and late outcomes |
| topic | neonatal brain damage traumatic brain injury ALS synuclein oligomerization Parkinson's disease |
| url | https://www.frontiersin.org/article/10.3389/fneur.2019.00635/full |
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