240 of observed clinical manifestations. However, recent evi- dence suggests that the true culprit of cellular toxicity may be the soluble cytoplasmic oligomeric α-synuclein protein, whereas the large insoluble protein aggregates may in fact represent a cellular defense mechanism in which the cell sequesters cytotoxic-soluble oligomeric proteins into insol- uble inclusion bodies [42]. Attempting to replicate the cardinal phenotypic features of PD, researchers have made use of animal models of dopaminergic neurotoxicity, and transgenic models of the familial PD-causing genes. In drosophila, overexpression of SNCA leads to age-dependent dopaminergic neuron degen- eration. Also, transgenic mice overexpressing mouse and human SNCA exhibit pathological phenotypes—inclusion body formation in some CNS cells, slight impairment in motor control, and loss of dopaminergic neuron terminals in the basal ganglia. These results from transgenic models support a causal role for α-synuclein in the development of PD [43–45]. Furthermore, the experiments using LRRK2-G2019S transgenic mouse models demonstrated age-dependent and levodopa-responsive slowness of movement associated with diminished dopamine release and axonal pathology [46]. Taking together this body of evidence and the known inherited forms of PD, one can construct a basic PD model: α-synuclein begins to aggregate, through some innate mech- anism, or induced by other factors; the cell recognizes the buildup of cytosolic α-synuclein levels and attempts to degrade the proteins by ubiquitination, and subsequent shut- tling to a proteasome for degradation. In the diseased brain, any one of the following processes could be disturbed: the innate dynamic aggregation of α-synuclein, the regulation of α-synuclein expression level, ubiquitination of α- synuclein, and degradation of α-synuclein degradation. In- terestingly, Lewy bodies generally contain high concentra- tions of ubiquitin, suggesting unfruitful attempts by the cellular proteasomal pathway to degrade α-synuclein de- spite substantial poly-ubiquitination. In sum, while it has been shown that overexpression of α- synuclein transgenes leads to protein aggregation in normal cells, the study of native processes leading to aggregation in affected individuals has been hindered by the inaccessibility of human neurons in vivo, the limitations inherent in studying postmortem samples from PD patients, and the inability to accurately recapitulate human disease in transgenic models [47–49]. Induced Pluripotent Stem Cells The development of human induced pluripotent stem cells (iPSCs) in 2007 by Takahashi et al. [50] and Yu et al. [51] has presented a novel approach to study human diseases. Curr Neurol Neurosci Rep (2012) 12:237–242 Where researchers were previously restricted to studying human proteins in virally induced overexpression animal models, or, at best, a zinc-finger cleaved recombination on a native promoter, we are now able to generate stable plu- ripotent lines from patients with inherited forms of disease, with their endogenous genome and its transcriptional feed- backs largely intact. To explore the potential use of iPSC-derived neurons in detecting protein accumulation and aggregation phenotypes, we selected two PD-causing genotypes: the homozygous G2019S point mutation in the LRRK2 gene, which causes autosomal-dominant PD, and the heterozygous triplication of the SNCA locus (total: four functional gene copies), which also causes autosomal-dominant PD. In keeping with a dominant mode of inheritance, in the vast majority of LRRK2-PD patients a single heterozygous G2019S muta- tion is present; however, rare patients with homozygous G2019S mutation have also been reported (mostly due to parental consanguinity), resulting in a similar phenotype. LRRK2-G2019S had previously been identified in 0.6– 1.6% and 2–8% of sporadic and familial PD, respectively [52–54]. The penetrance of this particular mutation is age- dependent, increasing from 17% penetrance at age 50–85% at age 70 years [55]. Clinical symptoms associated with PD in individuals carrying the LRRK2-G2019S mutation are mostly indistinguishable from those affected by late-onset idiopathic PD with pathologies affecting both motor and non-motor bodily functions [56]. α-Synuclein expression level is known to influence dis- ease progression with triplications causing earlier onset and more rapid progression than duplications [17, 49, 57, 58]. Due to this pronounced phenotype in patients, SNCA triplication genotype was selected to provide the highest probability of detecting disease-related phenotypes that may be useful in categorizing disease characteristics in patient-specific iPSC-derived neurons. Although derivation of iPSC lines from idiopathic PD patients has been reported, it is still not known whether these PD iPSCs can give rise to mDA neurons that exhibit native phenotypes related to PD in vitro [59, 60]. As PD is likely to result from a combination of genetic and environmental factors, it is not clear to what extent sporadic PD lines will demonstrate phenotypes that are clearly discernible; thus, proof-of-principle dem- onstrations that iPSC lines recapitulate key phenotypes of PD may be most effectively achieved using cells from patients with monogenic mutations. Recent work by Is- rael et al. [61 ] has demonstrated the utility of iPSC modeling for AD, suggesting iPSC modeling may be broadly applicable to neurodegenerative diseases. Gener- ation of PD phenotypes from iPSC-derived neurons would be useful for studies aimed at understanding dis- ease mechanism, prevention, and treatment.