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bioRxiv · 10.1101/2025.01.09.632283

Transgenic A53T mice have astrocytic α-synuclein aggregates in dopamine and striatal regions

Peat, C.·Prasad, A.·Finkelstein, D. I.·Sue, C.·Johnston, J.·Parish, C.·Thompson, L.·Kirik, D.·Halliday, G.
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Abstract

AimsParkinsons disease is considered biologically a neuronal -synuclein disease, largely ignoring the more widespread -synuclein deposition that occurs in astrocytes, with the aim of this study to identify whether astrocytes accumulate small -synuclein aggregates before or after neurons. MethodsFixed serial midbrain and striatal sections from M83 A53T transgenic mouse model of Parkinsons disease and wild-type controls were histologically processed for multiplex labelling of -synuclein and astrocytic markers and astrocyte quantitation performed on digital images using QuPath software. ResultsThe density of astrocytes within the substantia nigra pars compacta was approximately 30% greater compared with other sampled regions (P<0.005). Small aggregates of -synuclein were observed in astrocytic processes, including in wild-type mice where a quarter of all astrocytes had an obvious -synuclein aggregate. Compared to wild-type, A53T transgenic astrocytes had significantly enlarged somas (P<0.001) with more processes (P<0.001) consistent with a reactive phenotype. The A53T transgenic mice had more than double the numbers of astrocytes (P<0.001) and 2.5 times more astrocytes with -synuclein aggregates compared to wild-type mice (P<0.001). ConclusionsThese data suggest that small -synuclein aggregates are normally cleared by astrocytes and that the substantia nigra pars compacta requires more astrocytic support for this function than other midbrain dopaminergic regions or the striatum. This adds another vulnerability factor to those already known for the substantia nigra with early deficits in clearance of small -synuclein aggregates by astrocytes associated with an increased astrocytic reactivity in the A53T transgenic mouse model. Key PointsO_LIThe substantia nigra pars compacta contains a higher density of astrocytes than the ventral tegmental area or striatum, indicating a greater reliance on astrocytic function and a greater vulnerability to astrocyte dysfunction C_LIO_LISmall aggregates of -synuclein were observed in wild-type midbrain and striatal astrocytes, indicating normal clearance of -synuclein by these astrocytes C_LIO_LIMidbrain and striatal astrocytes from A53T transgenic astrocytes have more than double the number of astrocytes and more astrocytes containing -synuclein aggregates which have a reactive morphological phenotype. C_LI

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Peat, C., Prasad, A., Finkelstein, D. I., Sue, C., Johnston, J., Parish, C., Thompson, L., Kirik, D., Halliday, G.. 2025-01-12. Transgenic A53T mice have astrocytic α-synuclein aggregates in dopamine and striatal regions. https://doi.org/10.1101/2025.01.09.632283

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