Evaluating the effects of a novel PROTAC LRRK2 inhibitor on a Drosophila melanogaster model of Parkinson’s disease

Parkinson’s disease (PD) stands as a prominent human neurodegenerative disorder characterized by death of dopaminergic neurons oars compacta (SNpc) and the formation of insoluble intracellular inclusions of misfolded protein. The aetiology of PD is heterogeneous, and its pathogenesis is not completely understood, resulting in a limited repertoire of effective treatments. The predominant approach in PD therapeutics addresses symptomatic relief rather than directly altering the underlying neurodegeneration. While most PD cases are idiopathic, some cases exhibit genetic autosomal inheritance patterns. Among these, point mutations in the leucine-rich repeat kinase 2 (LRRK2) are the most common cause of autosomal inherited PD. They all are gain-of function mutations that cause an increased kinase activity of LRRK2. In this context and for therapeutic purposes, numerous LRRK2 inhibitors have been developed in recent years. Unfortunately, all currently available LRRK2 inhibitors are invariably associated with side effects, particularly affecting the pulmonary and renal systems. XL0126, a recently developed LRRK2 proteolysis targeting chimeras (PROTACs) is proposed as one of the most promising PD-modifying therapeutics. This compound conjugates LRRK2 inhibition with ubiquitylation and proteasomal degradation, thereby augmenting inhibitory efficacy, and mitigating the risk of potential side effects. In this work we evaluated for the first time the efficacy of XL01126 in a in vivo context. We assessed its capacity to ameliorate symptoms of two Drosophila melanogaster models of LRRK2-associated PD: flies expressing human LRRK2 wild-type (WT) or LRRK2 G2019S. The analysis comprehended the evaluation of the efficacy of XL01126 in rescuing locomotor impairment and neurodegeneration. In parallel, we used fly genetic to measure its activity on mitophagy levels in vivo.