Curr Neurol Neurosci Rep (2012) 12:237–242 neuroprotective effects, mitochondrial degeneration resis- tance, and neurotransmitter deficits [27, 28]. However, the importance of α-synuclein should not be underestimated; the presence and similarity of β-synuclein and γ-synuclein in these knockout animals may compensate for the deficien- cy of α-synuclein, masking critical processes that it is involved in. Recent studies on complete synuclein-knockout animals showed age-dependent neurological impairments with premature death [29]. While SNCA whole-locus multiplications (duplication or triplications) are perhaps the most relevant to sporadic patients, as they encode a qualitatively wild-type protein rather than a missense form, LRRK2 mutations are, by far, the most common inherited form of PD. Studies in animal and cellular models have shown that certain mutations in the LRRK2 gene can increase its kinase activity, which contrib- utes to neurotoxicity, possibly via the oxidative stress path- way [30–33]. Moreover, cells expressing mutant LRRK2 have been shown to be more vulnerable to peroxide- induced cell death than wild-type LRRK2 cells [6, 32]. Although the function of LRRK2 is currently not fully understood, there is evidence that the reduced expression of LRRK2 mRNA limits neural progenitor cell differentia- tion toward dopaminergic neurons and may enhance cell death [34]. These findings suggest that LRRK2 plays a pivotal role in neuronal survival, and that the loss of function in this gene might also be pathogenic for PD [35]. Models of Parkinson’s Disease To understand the development and progression of a human disease, an effective model that combines the genetic under- pinnings with a similar, if not identical, phenotypic output is required. The appreciable gaps in our understanding of the mechanisms of PD initiation and progression, along with other sporadic and genetic neurodegenerative diseases, can be traced to the current lack of accurate models of these complex human diseases. The standard process for model- ing human disease with genetic origins has been to over- express the human gene of interest in model organisms (from yeast, to drosophila, to mouse, to non-human primate) and then observe the cellular and protein response. Pertur- bations that appear phenotypic are used as the fitness func- tion for subsequent drug screening or therapeutic target selection. These studies have provided some important advances for a large spectrum of human disease, and have been instrumental in our basic understanding of neurode- generative diseases [33, 36–39]. However, the use of these transgenic models have failed to develop an accurate portrait of the underlying disease mechanisms. This unfortunate result should not be surprising. While overexpression of human genes in model organisms 239 may constitute an accurate representation of the under- lying human pathogenesis for some diseases, in complex neurodegenerative diseases that involve endogenously expressed human proteins, basic cellular machinery such as transcriptional feedback, and stochastic balance of the proteasomal pathway are bound to play significant roles. These two fundamental cellular processes are greatly com- promised in overexpression organism models: transcrip- tional feedback is impossible when proteins are expressed on a non-native promoter, or even a native promoter in a different location in the genome, where epigenetics and other sequence neighbor effects will undoubtedly play a role in expression. The result is that mechanistic studies of neurodegeneration have been thwarted by an inability to study the cellular processes in susceptible human neurons that had an endogenous predisposition to the disease. The lack of studies employing human cells to investigate human neurodegenerative disease is not due to a lack of interest. PD is challenging to study due to the inaccessibility of affected human midbrain dopaminergic (mDA) neurons and a scarcity of animal models that mimic the key disease features. The transgenic animals and cellular models expressing known PD-associated genes have provided im- portant insights into the pathogenesis of the disease; how- ever, it has been difficult to demonstrate that the implicated mechanisms are also present in neurons from affected individuals. Previous genetic studies have implicated several potential mechanisms but the pathogenesis of PD remains largely obscure. In most PD patients, Lewy bodies and Lewy neu- rites form in both CNS and autonomic PNS neurons. These large intracellular proteinaceous inclusions are rich in α- synuclein and ubiquitin, an observation that suggests a role for α-synuclein and the proteasome in the molecular devel- opment of sporadic and inherited PD [40]. However, not all patients with PD develop Lewy bodies. Although mutations in LRRK2 are commonly associated with PD and Lewy body pathology, some of these patients do not exhibit a Lewy phenotype. Therefore, it is thought that protein aggre- gration may actually be a disease modifier rather than direct cause [41]. Methods to identify patients with a well-defined aggregation phenotype may be useful in categorizing dis- ease, as well as in correctly targeting disease-modifying interventions to an appropriate class of patients. As discussed, autosomal-dominant forms of PD have been documented in families with SNCA missense muta- tions or gene duplication/triplications. α-Synuclein protein aggregation and markers of cellular stress are also seen in other neurodegenerative disorders, including multiple sys- tem atrophy, Bradbury-Eggleston syndrome, and dementia with Lewy bodies. The selective degeneration of neural subtypes in each disease has since been linked to the resulting cornucopia