Despite the presence of this genetic defect from birth onward, clinical symptoms take decades to become clinically evident. In addition, the identified human LRRK2 mutations show a clearly reduced penetrance. For example, the risk of PD for a person with an LRRK2 G2019S mutation GABA antagonist drugs that was investigated by Matta et al. (2012) increases with age. At the age of 59 it is 28%, at age 69
it is 51%, and at the age of 79 years it is 74% (Healy et al., 2008). One can therefore expect that the biological functions affected by the mutation are not essential and are likely to have only a very mild effect on important biological processes like synaptic transmission. The relatively mild effects even of complete deletion of LRRK expression in the study by Matta et al. (2012) are in line with this. Still, it is quite remarkable that despite the intense interest check details for LRRK2 and the availability of mutant mice and cell models for this kinase, the endocytosis defects have not been observed before, except for some scattered observations (Shin et al., 2008; Piccoli et al., 2011). In addition to the fact that the overall effects on synaptic transmission are mild, a second reason might be that the primary
goal of many researchers creating and studying animal models for neurodegeneration has been to recapitulate the clinical and pathological findings of the human disease. Unfortunately, not many such models exist despite a wide range of models generated in different species. One could therefore wonder whether it is even realistic to have these expectations. Maybe the differences between humans and animal species in, for example, brain organization and life span are simply too large? However, animal models do exist that each mimic different aspects of the disease such as the pathological aggregation of misfolded proteins like α-synuclein. Often this requires the construction of complex models like double or triple transgenics to show clear phenotypes, while the actual biological mechanisms resulting from the pathogenic mutations have received far less attention. Hence, considering
the expected effect size of the pathogenic mutations, the question arises whether the field has studied in enough molecular before detail the existing models and especially those models that mimic the human mutations or even the human genomic locus without overexpression or other additional manipulations. “
“The epilepsies are a diverse group of disorders in which seizures are the defining manifestation. Seizure initiation and spread in temporal lobe epilepsy (TLE), one of the most common and intractable epilepsies in adolescents and adults, is thought to involve medial temporal structures, such as the hippocampus, parahippocampal regions, and amygdala. These regions often display distinct histopathology, the hallmark of which is Ammon’s horn sclerosis (AHS).