James P. Bennett, Jr1,2., Paula M. Keeney1,2 (firstname.lastname@example.org), David G. Brohawn2,3(email@example.com), Amy C. Ladd2 (firstname.lastname@example.org), Knarik Arkun4 (email@example.com), Ann C. Rice2 (firstname.lastname@example.org), Ravindar R. Thomas2 (email@example.com).
1Neurodegeneration Therapeutics, Inc.
Charlottesville, Virginia, USA
2Virginia Commonwealth University Parkinson’s and Movement Disorders Center
3Virginia Commonwealth University Department of Medical Genetics
4Virginia Commonwealth University, Department of Pathology (Neuropathology)
Richmond, Virginia, USA
James P. Bennett, Jr. M.D., Ph.D.
Neurodegeneration Therapeutics, Inc.
3050A Berkmar Drive
Charlottesville, VA 22901-3450
Abstract: Human neurodegenerative diseases (NDD’s) are commonly age-related, mostly genetically sporadic (non-monogenic) in occurrence, complex in etiology and clinical presentations, and demonstrate clinical phenotypes of Alzheimer’s dementia (AD), or Parkinson’s disease (PD) or motor neuron disease (a.k.a. amyotrophic lateral sclerosis, ALS), among others. NDD’s exact increasing personal and societal burdens as populations age and disease-altering specific therapies remain elusive. We presented data that, at least in postmortem samples from clinically advanced NDD subjects, mitochondrial bioenergetic impairments are reflected in reduced expression of genes required for ATP production and mitochondrial RNA stability. Mitochondrial proteins and nucleic acids can be damaged by oxidative/nitrative stresses during aging, and such damage appears increased in age-matched postmortem NDD samples. Such “mitochondrial stress” may lead to increased release of mitochondrial DNA (mtDNA) into cytosol, activating the innate immune system through the cGAS-STING system. We discuss this possibility and present evidence that expressions of several interferon-stimulated genes (ISG’s) are increased in NDD brain samples. If present, cGAS-STING activation from mtDNA leakage could contribute to neuroinflammation seen in NDD brains and presents an additional potential therapeutic target.
Keywords: human neurodegenerative brain diseases, mitochondrial DNA, mitochondrial oxidative phosphorylation, oxidative stress, neuro-inflammation, interferon-stimulated gene expression, cGAS-STING
Neurodegenerative diseases (NDD’s) are characterized by clinical phenotypes that derive from neuronal dysfunction and degeneration. NDDs’ incidences generally increase with aging, occur sporadically except for rare monogenic variants that frequently are familial, exact increasing personal and societal tolls and are commonly causal for death of afflicted individuals. For the most common adult NDD’s, current estimates are that on a world-wide basis, about 30-35 million persons suffer from dementia caused by Alzheimer’s disease (AD), over 10 million suffer from Parkinson’s disease (PD), and about 450,000 are living with amyotrophic lateral sclerosis (ALS, a.k.a. motor neuron disease).
NDD’s are complex medical problems with likely multi-factorial etiologies. As a group, they are among the most debilitating of chronic illnesses of adults, have defied discovery of disease-altering therapies and appear to represent interactions between general brain aging processes and disease-specific molecular pathologies.
Because NDD’s likely appear pathologically over years/decades, chronic mechanisms compared to acute conditions (such as infections, strokes, drug toxicities, etc) are likely etiologic. Two contenders, among several possibilities, that have emerged over the last decade are progressive bioenergetic impairment due to mitochondrial damage and neuroinflammation mediated by the cGAS-STING double-stranded nucleic acid detection system.[1-13]
Mitochondrial bioenergetic deficits have been reported in human brain and animal/cellular models of NDD’s, including amyotrophic lateral sclerosis (ALS) [14-19], Alzheimer’s disease (AD) [14 18 20-29] and Parkinson’s disease (PD) [14 18 23 25 30-49]. These deficits in ATP production may arise from oxidative stress damage [15-17 19 50-53] (ALS); [20-23 26 28 29 51 52 54-65] (AD); and [23 33 34 36 38 39 41 43-45 47 48 51 52 66-72] (PD).
We presented gene expression data from our studies of postmortem NDD brain (AD, PD) and cervical spinal cord (ALS) tissues that support bioenergetic deficiencies in ATP production mediated by OXPHOS) [73-79] and activation of the cGAS-STING system (present study). We also reviewed biochemical and physiological studies from our group and others (see above) that have in toto allowed construction of the hypothesis that NDD’s arise over time from a combination of “wear and tear” on the brain mitochondrial bioenergetic machinery, which could lead to release of mitochondrial DNA (mtDNA) into neuronal cytosol [5 12 52], resulting in activation of the cGAS-STING innate immunity system mediated by increased expression of interferon-stimulated genes (ISG’s) [1-3 6 8-13]. Activation of the cGAS-STING system has been recently demonstrated in human motor neuron IPSC’s and ALS spinal cord homogenates . These ISG’s following cGAS-STING stimulation of expression can cause apoptosis of neurons through multiple mechanisms and can be blocked by recently described cGAS inhibitor small molecules. If this hypothesis is correct, then combined neuroprotective therapy could include mitochondrially concentrated, antioxidative drug(s) and cGAS inhibitor(s) [1-8 80 81].
Postmortem NDD tissues have reduced copy numbers of mitochondrial DNA (mtDNA)
Using quantitative PCR for several mtDNA genes, we showed reduced mtDNA copy numbers in laser-captured neurons of ALS cervical spinal cord  in the setting of heterogenous distributions of mtDNA’s in anterior motor neurons. We compared the distribution of mtDNA genes and also found an increase in ALS of deleted mtDNA species . In laser-captured isolated AD hippocampal pyramidal neurons  we compared distributions of mtDNA copy numbers and found an altered distribution of mtDNA gene levels. In PD samples, nigral neurons with Lewy bodies (LB+) had on average ~4-fold increased copy numbers of mtDNA compared to LB(-) neurons .
Postmortem NDD tissues show reduced expression of OXPHOS genes
By RT-qPCR (ALS, ) or RNAseq (ALS , AD  or PD ) expressions of mtDNA OXPHOS genes appear reduced in cervical spinal cord sections (ALS) or LCM-isolated motorneurons (ALS), frontal cortical ribbon (AD) or ventral midbrain (PD). These findings suggested that in all three adult NDD’s, synthesis of ATP is impaired.
Postmortem NDD (AD or PD) tissues show reduced expression of mtRNA stabilizing protein
Using RNAseq, we showed that AD (frontal cortical ribbon) and PD (ventral midbrain) postmortem brain tissues showed reduced expression of LRPPRC (, a.k.a. LRP130), a mtRNA stabilizing protein [74 84 85]. This finding suggested that at least part of the reduced expression of mtDNA OXPHOS genes we observed in AD and PD brains could derive from reduced mtRNA stability.
Elevated expression of selected Interferon-Stimulated Genes (ISG) is increased in postmortem AD and ALS tissues.
We used RNAseq analysis of postmortem AD, PD and ALS tissues to assess expression levels of 47 type I interferon-stimulated genes based on their involvement in apoptosis, immune modulation, cell attraction and adhesion, or antiviral and pathogen detection . The results are shown in Fig 1. From that list, we selected 12 genes (CASP4, BAK1, PLSCR1, XAF1, IRF5, IRF7, IL12, VEGFC, EGF1, OAS1, ISG15, ISG20) that exhibited the following expression patterns:
- Gene expression was found in tissues from all 3 diseases (ALS, AD, PD), and at least 2/3 genes showed expression > 100% of control
- Gene expression was found in 2 out of 3 diseases, and expression of least 1 out of 2 genes was > 200% of control.
We then performed 2-way ANOVA’s on these gene sets. We observed that the patterns of ISG expression elevation were significant for AD frontal cortical ribbon (n=9 CTL, 8 AD) (F=1, 191; p=0.0103) and ALS cervical spinal cord (n=6 CTL, 7 ALS) (F=1,143; p=0.0017) but not for PD ventral midbrain (n=7 CTL, 13 PD) (F=1, 227; p=0.3367). These results on small postmortem tissue sets indicate that expressions of type I interferon-stimulated genes  can be increased in some NDD’s, and that the cGAS-STING pathway may be overly activated in these diseases.
Release of double-stranded (ds) mtDNA into cell cytosol is viewed as a potent stimulant for activation of cGAS-STING innate immunity signaling, with increased transcription of multiple interferon-stimulated genes [1 2 4-8 10-13 81 86]. Such activation may play a role in neurodegeneration [2 8 10 12 86]. Mitochondrial bioenergetic deficits that can arise from oxidative stress damage to either OXPHOS proteins or mtDNA itself [52 77 86] may trigger neuronal apoptosis, which itself can be a potent activator of the cGAS-STING pathway .
In the present study, we have reviewed past studies that showed post-mortem brain (AD, PD) or cervical spinal cord (ALS) tissues and isolated neurons (ALS, ) from subjects who died with advanced clinical phenotypes showed evidence of both bioenergetic deficits (decreased expression of OXPHOS genes [74 79 87]) and possible mtRNA instability (decreased expression of mtRNA stabilizing protein ). We now show potential activation of the cGAS-STING pathway (increased ISG expression, present study).
Our studies are limited by small numbers of each disease type. Whether such changes are found in larger disease populations await examinations of those larger, heterogenous populations. Also, our findings shed no insight into the problem of selective vulnerability of neuronal populations in each pathological phenotype.
However, in spite of these important limitations, our findings suggest a unifying mechanism of neurodegeneration, composed of mitochondrial bioenergetic deficit, leading to apoptosis of neuronal populations, which results in a clinical phenotype that is worsened by neuroinflammation (cGAS-STING activation). If this formulation is relevant, then combination treatment with antioxidative stress agents, mitochondrial biogenesis activators and cGAS inhibitors could be therapeutic for multiple NDD’s.
This formulation of NDD etiology does not require designation of a particular “genesis event (or events)” that initiate(s) the neurodegenerative cascade. Instead, it is more pragmatic, in that it addresses pathophysiological processes that arise for whatever reason, and the “reasons” may vary from person-person.
All of the data presented in this paper has been previously published, as have the methods and subject demographics [73 74 76-79]. The data for construction of Figure 1 were derived from these prior studies and used GraphPad Prism v. 9.0.2 for statistical analyses.
Author Contributions: JPB participated in design of all experiments and wrote the manuscript draft. PMK supervised all AD and PD tissues and their RNA/DNA extractions. ACL and DGB participated in experiments involving analyses of ALS tissues. ACR and RRT participated in experiments involving laser capture and analyses of AD tissues. KA and ACR participated in experiments involving laser capture of PD substantia nigra Lewy body (+) and Lewy body (-) neurons. All authors have seen and agree with the final manuscript version.
Ethics Statement: No animals were used in these experiments. Human tissues were obtained either from a non-profit source that had their own IRB oversight (National Disease Research Interchange, Philadelphia, PA http://www.ndriresource.org; ALS/CTL cervical spinal cord), or under local IRB supervision (most AD/CTL and most PD/CTL), or were considered “autopsy tissue” and did not require IRB oversight (some AD/CTL and some PD/CTL). JPB is the inventor on US and EU patents regarding the use of R(+) pramipexole in NDD’s. The authors otherwise declare no competing interests.
Data Availability: RNAseq files that have had Illumina sequencing adapters removed (by Trimmomatic) are available free of charge to all academic and non-profit institutional investigators following queries directed to the corresponding author (JPB).
Figure 1. Figure 1 shows interferon-stimulated gene (ISG)  expression levels measured by RNAseq in postmortem tissue homogenates from Alzheimer disease (AD, red bars, frontal cortical ribbon), or Parkinson disease (PD, green bars, ventral midbrain), or amyotrophic lateral sclerosis (ALS, blue bars, cervical spinal cord), presented as mean % control values. 2-way ANOVA for each NDD (versus CTL) revealed p= 0.0103 (AD), p=0.3367 (PD) or p=0.0017 (ALS). See text for details.
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