Objective: To determine the effect of intrastriatal injection of alpha-synuclein (aSyn) preformed fibrils (PFFs) on sensorimotor and non-motor function in rats.

Background: The ideal animal model of Parkinson’s disease (PD) should have good face validity. In the CNS, it should exhibit aSyn pathology throughout multiple brain regions and progressive degeneration of nigrostriatal dopamine neurons. Behaviorally, it should show L-DOPA-reversible sensorimotor impairments and a host of non-motor deficits that result in a reproducible time course and magnitude. We recently optimized phosphorylated a-syn (pSyn) accumulation and nigrostriatal degeneration following intrastriatal injection of PFFs into rats using immunohistochemical methods. At 2m, peak pSyn accumulation in the ipsilateral substantia nigra pars compacta (SNpc) occurs whereas loss of tyrosine hydroxylase (TH) SNpc neurons peaks 6m post injection(~50%) and is accompanied by modest deficits in contralateral forelimb use. In the present study we sought to amplify sensorimotor and non-motor function deficits by increasing striatal distribution and injection quantity of aSyn PFFs.

Method: Male Fischer 344 rats were injected unilaterally in the striatum with a total of 24μg aSyn PFFs into 3 sites or an equal volume of saline. Sensorimotor function was assessed using behavioral tests sensitive to varying degrees of SNpc neurodegeneration and several non-motor tests including assays for cognition, emotional reactivity, olfaction, and sleep. HPLC assessment of cortical and striatal monoamines and immunohistochemical analysis of nigrostriatal degeneration is ongoing.

Results: At 6m, PFF rats displayed significant movement and somatosensory asymmetries compared to control rats. Time to initiate a forelimb step and time to contact an adhesive stimulus on the forepaw were significantly longer for the contralateral limb compared to the ipsilateral limb. Further, hindlimb stepping in the cylinder was significantly reduced in PFF rats compared to controls and L-DOPA administration reversed movement initiation deficits. Cognitive function was also affected in the PFF rats, with investigation time significantly decreased in an object recognition test.

Conclusion: Establishment of a-syn PFF surgical parameters resulting in motor and non-motor deficits will facilitate preclinical assessment of novel disease-modifying therapies

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MDS Abstracts - https://www.mdsabstracts.org/abstract/intrastriatal-injection-of-alpha-synuclein-preformed-fibrils-results-in-cognitive-dysfunction-and-l-dopa-reversible-sensorimotor-impairments-in-rats/