Phelan-McDermid syndrome (PMS) is a rare genetic condition that causes global developmental disability, delayed or absent speech, and an autism spectrum disorder. The loss of function of one copy of ...SHANK3, which codes for a scaffolding protein found in the postsynaptic density of synapses, has been identified as the main cause of PMS. We report the generation and characterization of two induced pluripotent stem cell (iPSC) lines derived from one patient with a SHANK3 mutation and the patient’s mother as a control. Both lines expressed pluripotency markers, differentiated into the three germ layers, retained the disease-causing mutation, and displayed normal karyotypes.
Several mutations that cause Parkinson's disease (PD) have been identified over the past decade. These account for 15-25% of PD cases; the rest of the cases are considered sporadic. Currently, it is ...accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes. While rodent models exist for some of the PD-causing mutations, research on the sporadic forms of PD is lagging due to a lack of cellular models. In our study, we differentiated PD patient-derived dopaminergic (DA) neurons from the induced pluripotent stem cells (iPSCs) of several PD-causing mutations as well as from sporadic PD patients. Strikingly, we observed a common neurophysiological phenotype: neurons derived from PD patients had a severe reduction in the rate of synaptic currents compared to those derived from healthy controls. While the relationship between mutations in genes such as the SNCA and LRRK2 and a reduction in synaptic transmission has been investigated before, here we show evidence that the pathogenesis of the synapses in neurons is a general phenotype in PD. Analysis of RNA sequencing results displayed changes in gene expression in different synaptic mechanisms as well as other affected pathways such as extracellular matrix-related pathways. Some of these dysregulated pathways are common to all PD patients (monogenic or idiopathic). Our data, therefore, show changes that are central and convergent to PD and suggest a strong involvement of the tetra-partite synapse in PD pathophysiology.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease with an incidence rate increasing vastly with age. Clinical symptoms include bradykinesia, tremor, rigidity, and ...postural instability caused mainly by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and degradation of the nigrostriatal dopaminergic pathway, both causing a reduction in brain dopamine levels. Other non-motor symptoms such as depression, impaired olfactory functions, constipation, urinary dysfunction, and a decrease in respiratory muscle strength may also be present in PD. The pathology of PD may consist of aggregates of Lewy bodies (LB) consisting mainly the αsynuclein protein, although a diagnosis of PD could occur without the presence of LB. 10-15% of PD patients can be assigned to several genetic risk factors that have shown a direct link to the pathology of the disease with described mechanisms, compared to approximately 85% of the patients that are diagnosed with idiopathic Parkinson's disease (IPD), without a known genetic or familial cause. The lack of data due to the inability to study cellular models for IPD until the introduction of induced pluripotent stem cell (iPSC) technology had preventative and therapeutic implications on a large percentage of PD patients and further research with these new techniques can improve diagnosis and treatment of PD. In this study, I have grown midbrain neurons from human iPSCs and compared between healthy and IPD individuals to search for differences between the two groups using immunohistochemistry methods focusing on extracellular matrix proteins due to preliminary data in the lab that this pathway is highly implicated in PD.
