Affiliations: [a] University of Maryland-Baltimore, Baltimore, MD, USA
| [b] University of California at Los Angeles, Los Angeles, CA, USA
| [c] German Center for Neurodegenerative Disease (DZNE), Bonn, Germany
| [d] Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Correspondence:
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Corresponding authors: Iris Lindberg, PhD, Department ofAnatomy and Neurobiology, University of Maryland MedicalSchool, University of Maryland-Baltimore, Baltimore, MD 21201, USA. Tel.: +1 410 7064778; E-mail: ilindberg@som.umaryland.edu; Nigel T. Maidment, PhD, Department of Psychiatry and Biobehavioral Sciences, Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90024, USA. Tel.: +1 310 206 7767; E-mail:nmaidmen@ucla.edu.
Note: [1] These authors contributed equally to this work.
Abstract: Background:Parkinson’s disease involves aberrant aggregation of the synaptic protein alpha-synuclein (aSyn) in the nigrostriatal tract. We have previously shown that proSAAS, a small neuronal chaperone, blocks aSyn-induced dopaminergic cytotoxicity in primary nigral cultures. Objective:To determine if proSAAS overexpression is neuroprotective in animal models of Parkinson’s disease. Methods:proSAAS- or GFP-encoding lentivirus was injected together with human aSyn-expressing AAV unilaterally into the substantia nigra of rats and motor asymmetry assessed using a battery of motor performance tests. Dopamine neuron survival was assessed by nigral stereology and striatal tyrosine hydroxylase (TH) densitometry. To examine transsynaptic spread of aSyn, aSyn AAV was injected into the vagus of mice in the presence of AAVs encoding either GFP or proSAAS; the spread of aSyn-positive neurites into rostral nuclei was quantified following immunohistochemistry. Results:Coinjection of proSAAS-encoding lentivirus profoundly reduced the motor asymmetry caused by unilateral nigral AAV-mediated human aSyn overexpression. This was accompanied by significant amelioration of the human aSyn-induced loss of both nigral TH-positive cells and striatal TH-positive terminals, demonstrating clear proSAAS-mediated protection of the nigrostriatal tract. ProSAAS overexpression reduced human aSyn protein levels in nigra and striatum and reduced the loss of TH protein in both regions. Following vagal administration of human aSyn-encoding AAV, the number of human aSyn-positive neurites in the pons and caudal midbrain was considerably reduced in mice coinjected with proSAAS-, but not GFP-encoding AAV, supporting proSAAS-mediated blockade of transsynaptic aSyn transmission. Conclusion:The proSAAS chaperone may represent a promising target for therapeutic development in Parkinson’s disease.
