-Synuclein protein aggregation and markers of cellular stress are also seen in other neurodegenerative disorders including dementia with Lewy bodies, pure autonomic failure, and multiple system atrophy[16]. of markers of oxidative stress, and sensitivity to peroxide induced oxidative stress. These findings show that the dominantly-acting PD mutation is intrinsically capable of perturbing normal cell function in culture and confirm that these features reflect, at least in part, a cell autonomous disease process that is independent of exposure to the entire complexity of the CaMKII-IN-1 diseased brain. == Introduction == Parkinson’s Disease (PD) is a debilitating neurodegenerative disorder characterized by the loss of neurons in both the peripheral and central nervous system[1],[2],[3],[4],[5],[6]. The majority of cases result from unknown etiology causing widespread neuron loss in the midbrain, cerebral cortex, olfactory bulb, and peripheral nervous system. Neuron degeneration is pronounced in the dopaminergic neurons of the substantia nigra pars compacta leading to the diagnostic clinical features of bradykinesia, rigidity and tremor[1],[2],[3],[4],[5],[6],[7]. Genetic studies have implicated several potential mechanisms but the etiology of Parkinson’s disease remains obscure. In a large cohort of patients, Lewy bodies and Lewy neurites form in CNS and autonomic peripheral nervous system (PNS) neurons. These large intracellular proteinaceous inclusions are rich in -synuclein and ubiquitin, an observation that suggests a role for -synuclein and the proteasome in the molecular development of sporadic and genetic PD[8]. However, not all patients with PD develop Lewy bodies. Although alterations in LRRK2 are commonly associated with PD, many of these patients do not exhibit a Lewy phenotype and it is thought that protein aggregration may be a disease modifier[9]. Methods to identify patients with an intrinsic aggregration phenotype may be useful in categorizing disease as well as in correctly targeting disease-modifying interventions to an appropriate class of patients. To explore the potential use of iPSC-derived neurons in detecting protein accumulation and aggregation phenotypes, we report the generation of iPSCs from a patient with a dominant autosomal form of PD caused by triplication IL9 antibody of theSNCAlocus. Dosage is known to influence disease progression with triplications causing earlier onset and more rapid progression than duplications ofSNCA[10],[11],[12],[13]. Given their pronouncedin vivophenotype,SNCAtriplications were selected to provide the highest probability of detecting disease-related phenotype that may be useful in categorizing disease characteristics in patient-derived neurons. Familial autosomal dominant forms of PD have been documented in families withSNCAmutations or gene duplication/triplications as well as in families with mutations in proteins regulating the ubiquitin-proteasome pathway[11],[14],[15]. -Synuclein protein aggregation and markers of cellular stress are also seen in other neurodegenerative disorders including dementia with Lewy bodies, pure autonomic failure, and multiple system atrophy[16]. Although overexpression of -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 neuronsin vivo, the limitations inherent in studying postmortem samples from PD patients, and the inability to accurately recapitulate human disease in transgene models[12],[17]. Here we report that neurons derived from a SNCA triplication patient exhibit intrinsic protein accumulation and aggregation phenotypes. == Results == == Patient Clinical Presentation == The subject of this study was CaMKII-IN-1 a 48-year-old male with CaMKII-IN-1 anSNCAtriplication (Trpl-HDF). The patient presented with early onset, autosomal dominant, PD at age 38. The patient was left-handed and had been in excellent health most of his life. His initial symptoms in 2007 were fatigue, tremor and decreased dexterity. At that time, he was not experiencing any changes in speech, gait or cognition. He had undergone an MRI scan, which was unremarkable. He exhibited a resting and mild intention tremor, but his gait was normal. Thus, in 2007, the patient CaMKII-IN-1 appeared to have mild Parkinson’s disease and no medication was required. At the time of the clinical examination in summer 2008, the patient noted mild problems with recent memory. He did not experience any psychiatric symptoms such as delusions or hallucinations but reported some anxiety and slight depression. He also reported urinary urgency and occasional constipation. He indicated that he had normal sleep patterns.