Abstract
There is still no cure for Parkinson's disease (PD), and we desperately need treatment that addresses the cause of the disease and modifies its clinical course. One of the main histologic hallmarks of PD is the apparition of Lewy bodies. These structures are mainly composed of aggregated a-synuclein (a-syn), involved in toxic processes, leading to mitochondrial dysfunction and degeneration of dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc). SLP-2 is a protein located inthe inner mitochondrial membrane and acts as a scaffold protein regulating mitochondrial function, integrity and bioenergetic. Previous results from our team showed that SLP-2 protein expression is reduced in DA neurons of human PD post-mortem brains.
Objective: We aimed to test the hypothesis that targeted SLP-2 overexpression (OE) in the DA neurons of the SNpc will confer protection against a-syn toxicity.
Methods: We unilaterally injected an AAV encoding a Cre-dependant human SLP-2 into the SNpc of DAT-Ires-Cre mice. Simultaneously, another AAV that overexpresses the human A53T a-syn or control AAV was co-injected We performed a motor assessment using the cylinder and pole tests 15-week post-injection. The following week, the mice were sacrificed, and DA neurons in the SNpc were
quantified by stereology using TII and NeuN markers, whereas their axonal density in the striatum was measured using the signal intensity for TH immunofluorescence. Inparallel, mitochondrial oxygen consumption into the SNpc was measured by high-resolution respirometry and human iPSC-derived DA neurons carrying A53T a-syn were used to reveal the role of SLP-2 on mitochondrial functions.
Results: Cylinder and pole tests revealed that targeted SLP-2 OE in the DA neurons of the SNpc rescued the motor deficits induced by a
syn toxicity by preventing DA denervation in the striatum andthe loss of TH+ and NeuN+ cell bodies in the SNpc. We also found that a syn induction is decreasing mitochondrial oxygen consumption by altering mitochondrial morphology and membrane potential. However, those deficits are restored by SLP-2 forced expression, indicating that SLP-2 can mitigate a-syn toxicity by rescuing mitochondrial functions.
Conclusion: Our results indicate that SLP-2 OE can protect DA neurons against a-syn toxicity and neurodegeneration. SLP-2 could thus represent a novel neuroprotective treatment against synucleinopathies and PD.