RT Journal Article
SR Electronic
T1 The proSAAS chaperone provides neuroprotection and attenuates transsynaptic α–synuclein spread in rodent models of Parkinson’s disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.09.29.462435
DO 10.1101/2021.09.29.462435
A1 Iris Lindberg
A1 Zhan Shu
A1 Hoa Lam
A1 Michael Helwig
A1 Nur Yucer
A1 Alexander Laperle
A1 Clive Svendsen
A1 Donato A. Di Monte
A1 Nigel T. Maidment
YR 2021
UL http://biorxiv.org/content/early/2021/10/01/2021.09.29.462435.abstract
AB Parkinson’s disease is a devastating motor disorder involving the aberrant aggregation of the synaptic protein synuclein (aSyn) and degeneration of the nigrostriatal dopaminergic tract. We previously showed that proSAAS, a small secreted chaperone protein widely expressed in neurons within the brain, is able to block aSyn-induced dopaminergic cytotoxicity in primary nigral neuron cultures. We show here that coinjection of proSAAS-encoding lentivirus profoundly reduced the motor asymmetry caused by unilateral nigral AAV-mediated human aSyn overexpression. This positive functional outcome was accompanied by significant amelioration of the human aSyn-induced loss of both nigral tyrosine hydroxylase-positive cells and striatal tyrosine hydroxylase-positive terminals, demonstrating clear proSAAS-mediated protection of the nigro-striatal tract. ProSAAS overexpression also reduced the content of human aSyn protein in both the nigra and striatum and reduced the loss of tyrosine hydroxylase protein in both regions. Since proSAAS is a secreted protein, we tested the possibility that proSAAS is able to block the transsynaptic spread of aSyn from the periphery to the central nervous system, increasingly recognized as a potentially significant pathological mechanism. The number of human aSyn-positive neurites in the pons and caudal midbrain of mice following administration of human aSyn-encoding AAV into the vagus nerve was considerably reduced in mice coinjected with proSAAS-encoding AAV, supporting proSAAS-mediated blockade of transsynaptic aSyn transmission. We suggest that proSAAS may represent a promising target for therapeutic development in Parkinson’s disease.Significance This paper describes two independent avenues of research that both provide support for the in vivo neuroprotective function of this small chaperone protein. In the first approach, we show that proSAAS overexpression provides remarkably effective protection against dopaminergic neurotoxicity in a rat model of Parkinson’s disease. This conclusion is supported both by three independent assays of motor function as well as by quantitative analysis of surviving dopaminergic neurons in brain areas involved in the control of motor function. In the second line of research, we show that in mice, the spread of human synuclein across synapses can be blunted by proSAAS overexpression.Competing Interest StatementThe authors have declared no competing interest.AAVadeno-associated virusaSynalpha synucleincMBcaudal midbrainDAdopamineDMVdorsal motor nucleus of the vagusGFPgreen fluorescent proteinMOmedulla oblongataNTSnucleus tractus solitariusrMBrostral midbrainSNcsubstantia nigra pars compactaTHtyrosine hydroxylase