Enforced DNA repair enzymes rescue neurons from apoptosis induced by target deprivation and axotomy in mouse models of neurodegeneration

Abstract

It is unknown whether DNA damage accumulation is an upstream instigator or secondary effect of the cell death process in different populations of adult postmitotic neurons in the central nervous system. In two different mouse models of injury-induced neurodegeneration characterized by relatively synchronous accumulation of mitochondria, oxidative stress, and DNA damage prior to neuronal apoptosis, we enforced the expression of human 8-oxoguanine DNA glycosylase (hOGG1) and human apurinic-pyrimidinic endonuclease/Ref1 (hAPE) using recombinant adenoviruses (Ad). Thalamic lateral geniculate neurons and lumbar spinal cord motor neurons were transduced by Ad-hOGG1 and Ad-hAPE injections into the occipital cortex and skeletal muscle, respectively, prior to their target deprivation- and axotomy-induced retrograde apoptosis. Enforced expression of hOGG1 and hAPE in thalamus and spinal cord was confirmed by western blotting and immunohistochemistry. In injured populations of neurons in thalamus and spinal cord, a DNA damage response (DDR) was registered, as shown by localization of phospho-activated p53, Rad17, and replication protein A-32 immunoreactivities, and this DDR was attenuated more effectively by enforced hAPE expression than by hOGG1 expression. Enforced expression of hOGG1 and hAPE significantly protected thalamic neurons and motor neurons from retrograde apoptosis induced by target deprivation and axotomy. We conclude a DDR response is engaged pre-apoptotically in different types of injured mature CNS neurons and that DNA repair enzymes can regulate the survival of retrogradely dying neurons, suggesting that DNA damage and activation of DDR are upstream mechanisms for this form of adult neurodegeneration in vivo, thus identifying DNA repair as a therapeutic target for neuroprotection.

Mitochondria Initiate and Regulate Sarcopenia

“…The apoptotic disassembly of motor neurons could begin regionally near dysfunctional mitochondria and spread to a wider area, resulting in motor neuronal death. Our speculation is supported from data that show that in aging-associated neural diseases, there is a loss of mitochondrial function leading to increased mPTP sensitivity, and attenuated mitophagy that contributes to apoptosis (32, 68, 86, 99, 111). Nevertheless, we do not have data to support a process of aging associated localized motor neuron disassembly outside of neural degenerative disease.…”

“…In neurons, DNA damage precedes neuronal apoptosis (85), whereas forced repair of DNA damage rescues neurons from elimination by apoptosis (86). Indeed, increased mtDNA mutations have been found in fiber regions that contain oxidative damage (2, 90).…”

“…Furthermore, aging-induced mtDNA deletions are closely associated with a loss of mitochondrial function in motor neurons (123), neuronal malfunction in diseases like Parkinson’s disease (115), and muscle loss with aging (50, 91). While elevated ROS production is not solely the result of mtDNA deletions or mtDNA mutations (141), it is clear that this mechanism contributes to mitochondrial ROS production in aging muscles and neurons (26, 86, 91). …”

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

“…In addition to SMA motor neurons (this study), accumulation of phospho-p53 S15 has been documented in human stem cell-derived motor neurons from C9ORF72-related ALS patients (Lopez-Gonzalez et al, 2016) and that of phospho-p53 S18 in neonatal axotomized mouse motor neurons (Martin and Wong, 2017). However, the functional relevance of this specific modification for the neurodegenerative process was not previously investigated in any disease models.…”

Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?

“…In a recent study, a neuroprotective role of BER machinery was demonstrated in mouse model. Martin et al enforced expression of human APE1 and OGG1 in vulnerable neurons and found that the expression significantly suppressed the axotomy and target deprivation induced apoptosis of thalamic neurons and motor neurons, which indicates that the modulation of DNA repair could be a potential therapeutic target for DNA damage related neuronal apoptosis [244]. Another study revealed that, overexpression of sirtuin 6 (SIRT6), which is down-regulated in brains of AD patients as well as 5XFAD mice, likely regulated by Aβ42, prevents Aβ42-induced DNA damage in a p53-depedent manner [244, 245].…”