Advances in new animal models of Parkinson's disease through antisense therapies

2019 edition

Rubén Pavia-Collado

Parkinson’s disease is characterized by progressive brain pathology affecting several neurotransmission systems, leading to a diverse profile of autonomic, motor, cognitive and psychiatric dysfunctions. Among them, depression and cognitive impairment are determinant factors in the quality of patient’s life and eventually can lead to dementia development. Despite the progress in the treatment of motor symptoms, there are not significant advances towards effective treatments of cognitive and psychiatric dysfunctions.

The fact that only 10-15% of patients have familiar background suggests that most cases have a complex etiology. Some mutations have been described to lead to earlier, more severe forms of PD, compared to non-genetic forms. Specifically, several mutations have been detected on α-synuclein (A53T, A30P), as well as duplications and triplications; other genes involved in familiar forms also include PARK2, PINK1, DJ-1 and LRRK2.

However, the existing models of Parkinson’s disease show important limitations to mimic this disorder, evaluating neurodegeneration as well as motor and non-motor alterations. Here, we used three mouse models overexpressing human proteins: 1) wild-type α-synuclein through a viral vector (AAV5), 2) mutant α-synuclein (*A30P*A53T), and 3) mutant LRRK2 (*G2019S) in order to systematically examine the impact of these models on dopaminergic neurotransmission as well as on motor, emotional and cognitive behaviors. We also evaluated the efficacy of an indatraline-conjugated antisense oligonucleotide (IND-ASO) to reduce α-synuclein expression of the three models.

*A30P*A53T mice showed reduced veratridine-induced dopamine release (-51%) and increased amphetamine-induced levels (+285%) in the striatum, and they also exhibited severe alterations of motor behavior. LRRK2 mice showed increased striatal dopamine concentration after local nomifensine infusion (+190%) together with cognitive deficits in the short-term memory. AAV5 mice displayed reduced striatal dopamine levels after veratridine (-86%) and nomifensine (-54%) infusion. AAV5 mice displayed altered motor and anxiety-like behaviors as well as cognitive deficits. Intracerebroventricular IND-ASO administration (100µg/day, 28 days) reduced α-synuclein expression in *A30P*A53T and AAV5 mice. In conclusion, these Parkinson’s disease models could be useful to mimic different stages of the disorder, providing a better understanding of the pathophysiology of the disease, being also useful to evaluate new therapeutic approaches.