Novel Neuronal Trigger for Neuroinflammation and Propagated Neurodegeneration in ALS
Asli Sahin1,Steve Rodriguez1, Mark W. Albers1* 1Department of Neurology, Massachusetts General Hospital, Boston, MA *Corresponding Author
Neuroinflammation is a pathologic hallmark of Amytotrophic Lateral Sclerosis (ALS). Type I interferon (IFN-I) is one innate immune pathway upregulated in most ALS brains. Cytoplasmic double-stranded RNA (cdsRNA), a pathogen associated molecular pattern (PAMP) in the context of viral infection, has long been known to invoke IFN-I and neuronal death. Our preliminary work has revealed that cdsRNA accumulates in neurons of the cerebellum and frontal cortex in postmortem ALS brains with C9ORF72 expansions via traditional immunohistochemistry (IHC) and novel cyclic immunofluoresence (cycIF) methods. Isolation of cytoplasmic dsRNA from these brains indicates that the hexanucleotide expansion contributes to the pool of cdsRNA, but is not the predominant species. We hypothesize that the accumulation of cdsRNA leads to innate immune activation and the death of neurons in one subtype of adult-onset neurodegenerative diseases. To test this hypothesis, we replicated cdsRNA mediated IFN-I and neuronal death in human neurons in a dose-dependent manner in vitro. In parallel, we discovered that neuronal-restricted transcription of genomic rearrangements, e.g. inversions introduced during transgene integration, in multiple mouse models cause propagation of type I neuroinflammation to adjacent and connected neurons. The propagated neuronal death in these models maps precisely to this pattern of neuroinflammation and is independent of the protein expressed by the transgene. dsRNA in these mouse lines was stable for >30 days after suppressing the transgene expression via doxycycline. We isolated cRNA via immunoprecipitation with an antibody against dsRNA and sequenced (dsRNA-seq) from affected and non-affected ALS brain regions. In ALS brains, we hypothesize that the cdsRNA will map, at least in part, to age-exacerbated processes, such as genomic instability, latent viral reactivation, and derepression of endogenous repeat elements, such as retrotransposons. Identification of the origins of cdsRNA in these mouse models and humans brain with neurodegeneration will elucidate the underlying mechanisms of action of genomic lesions to induce neurodegeneration.
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