Implicación de las caspasas-3 y -8 en el trastorno del espectro autista y la enfermedad de Parkinson

Abstract

Autism spectrum disorder (ASD) and Parkinson's disease (PD) are two neurological disorders that produce an important socioeconomic impact and a heavy burden for both patients and their families. These two disorders have in common the involvement of the DAergic system. It has been shown that killer caspases, including caspase-3 and caspase-8, have many other functions apart from their involvement in apoptosis phenomena. For example, our study is the first one to address that killer caspases play an important role in the development and the homeostasis of the DAergic system. Considering this background, we studied two knock-out (KO) animal models in the catecholaminergic lineage (Caspase 3 f/d TH-IRES-Cre and Caspase 8 f/d TH-IRES-Cre) to elucidate the role of these enzymes in the functionality of the DAergic system and their possible implication in ASD and PD. Our study shows important alterations in DAergic pathways in both animal models, mainly in the nigro-striatal pathway, although possible changes in the mesolimbic and mesocortical pathways are presumed. In addition, animals lacking caspase-3 and caspase-8 showed robust phenotypic features congruent with ASD, mainly behavioural, although we also observed biochemical aspects of this disorder that could justify their main symptoms. Therefore, we conclude that caspase-3 or caspase-8 depletion in the catecholaminergic lineage could lead to an animal model that mimics biomolecular and behavioural aspects of the disease. On the other hand, the death of DAergic neurons is the main neuropathological characteristic of PD and the main cause of its motor symptoms. Likewise, there is evidence of extrinsic and intrinsic apoptosis with the involvement of caspase-3 and -8 during the disease. For our study, we used a sub-acute MPTP model of PD in strains lacking caspase-3 and -8, which caused permanent symptoms of the disease by inducing death of DAergic neurons in the SN. Taking into account the involvement of killer caspases in the apoptosis phenomena and in the regulation of cell death, it was postulated that the absence of either caspase-3 or - 8 in the catecholaminergic lineage could protect against DAergic depletion. However, our study shows that absence of caspase-3 or caspase-8 does not protect against DAergic depletion after MPTP treatment, due to other cell death phenomena continue in development. In fact, the absence of caspase-3 seems to be especially detrimental, since in these conditions neuronal death switch to necrosis, with important associated inflammatory phenomena along with greater DAergic degeneration. On the contrary, caspase-8 absence does not produce changes in neuronal degeneration, since an intrinsic apoptotic occurs, although avoiding the inflammatory response.