Viral mediated α-synuclein overexpression results in greater transgene levels and α-synuclein overload in mice bearing kinase dead mutation of LRRK2

Mar 23, 2025Scientific reports

Higher alpha-synuclein levels from viral overexpression in mice with inactive LRRK2 kinase mutation

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Regenerative Health on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

AAV-h-A53Tα-syn-injected KD mice showed a decline in stepping activity compared to baseline levels.

Mice with the D1994S kinase-dead mutation of LRRK2 exhibited increased levels of phosphorylated α-synuclein in specific brain regions.
Total α-synuclein levels were elevated in the substantia nigra of LRRK2 KD mice following AAV-h-A53Tα-syn injection.
No significant degeneration of dopaminergic neurons was observed in the nigrostriatal pathway of LRRK2 KD mice.
The findings suggest that impaired kinase activity may lead to increased α-synuclein accumulation without affecting neuron survival.
The results could imply a potential link between LRRK2 mutations and altered α-synuclein dynamics.

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The relationship between mutations and susceptibility to synuclein pathology in Parkinson's disease (PD) is still unclear. We here investigate whether the mice carrying the D1994S kinase-dead (KD) mutation of LRRK2 show enhanced susceptibility to synucleinopathy. Twelve-month-old LRRK2 KD and WT mice were injected with AAV2/9 carrying human A53T α-synuclein (AAV-h-A53Tα-syn) or AAV2/9-GFP as a control. Three months after injection, α-synuclein pathology and nigrostriatal dopaminergic neuron degeneration were assessed along with motor behaviour. AAV-h-A53Tα-syn-injected LRRK2 KD mice showed a decline in stepping activity in the drag test compared to baseline levels and AAV-GFP-injected controls. This was associated with higher transgene levels and Serine129 α-syn phosphorylation in striatum and substantia nigra measured by immunohistochemistry. Total α-synuclein levels were also elevated in the substantia nigra but not striatum of AAV-h-A53Tα-syn LRRK2 KD mice compared to AAV-h-A53Tα-syn controls. Stereological counting of nigral dopaminergic neurons and densitometric analysis of striatal dopaminergic terminals did not reveal overt nigrostriatal degeneration. We conclude that silencing of kinase activity results in greater α-syn load due to greater viral transduction and/or defective α-syn clearance, possibly related to autophagy-lysosomal pathway impairment, however, with no consequence upon dopaminergic neuron survival in the mouse.

Key numbers

50%

Increase in h-A53Tα-syn Load

Compared to wild-type mice injected with AAV-h-A53Tα-syn.

8.27 ± 0.29

Motor Activity Decline

Measured in the drag test before AAV injection.

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Viral mediated α-synuclein overexpression results in greater transgene levels and α-synuclein overload in mice bearing kinase dead mutation of LRRK2

Abstract

Key numbers

Full Text

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