Variants in <i>Lrrk2</i> and <i>Snca</i> deficiency do not alter the course of primary encephalitis due to neurotropic reovirus T3D in newborn mice

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Variants of the leucine-rich repeat kinase-2 ( LRRK2 ) and α-synuclein ( SNCA ) genes are associated with Parkinson’s disease risk. We previously demonstrated that two Lrrk2 knock-in variants as well as Snca expression alter survival rates from combined pneumonitis and encephalitis following intranasal inoculation of newborn mice with a double-stranded RNA virus: respiratory-enteric-orphan virus, serotype-3 strain Dearing (reovirus T3D). Here, we examined whether outcomes of direct inoculation of the brain by reovirus T3D, which invariably causes lethal encephalitis within 15 days, would also be modified by variants in Lrrk2 and Snca . When we inoculated newborn mice intracerebrally with 5×10 2 plaque-forming units of reovirus T3D, we found that, when compared to wild-type littermates, Lrrk2 p.G2019S mutant mice and kinase-dead p.D1994S mutant animals showed the same time-to-death intervals post-infection, revealed no sex difference, and had similar viral titres in the brain. Furthermore, the reduction or absence of endogenous α-synuclein also did not alter the course of encephalitis in parallel studies. These outcomes are in contrast to those following the intranasal inoculation paradigm of newborn mice, in which Lrrk2 and wild-type α-synuclein were both protective in infection outcomes. Together, these findings suggest that the Parkinson’s disease-linked Lrrk2 and Snca genes contribute predominantly to systemic, innate responses by the host following reovirus T3D exposure.

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