Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson’s disease. We created a LRRK2 transgenic mouse model that recapitulates cardinal features of the disease: an age-dependent and levodopa-responsive slowness of movement associated with diminished dopamine release and axonal pathology of nigrostriatal dopaminergic projection. These mice provide a valid model of Parkinson’s disease and are a resource for the investigation of pathogenesis and therapeutics.

In this study we examined the effect of dopaminergic modulation on learning and memory.Parkinson's patients were tested 'on' versus 'off' dopaminergic medication, using a two-phase learning and transfer task. We found that dopaminergic medication was associated with impaired learning of an incrementally acquired concurrent discrimination task, while patients withdrawn from dopaminergic medication performed as well as controls. In addition, we found a dissociation of the effect of medication within a single two-phase task: patients tested 'on' medication were not impaired at the ability to generalize based on learned information. The deficit among medicated patients appeared to be related specifically to the concurrent, incremental, feedback-based nature of the task: such a deficit was not found in a version of the task in which demands for concurrent error-processing learning were reduced. Taken together with a growing body of evidence emphasizing a role for midbrain dopamine in error-correcting, feedback-based learning processes, the present results suggest a framework for understanding previously conflicting results regarding the effect of medication on learning and memory in Parkinson's disease.

Mutations in PTEN-induced kinase 1 (PINK1), a mitochondrial Ser/ Thr kinase, cause an autosomal recessive form of Parkinson's disease (PD), PARK6. To investigate the mechanism of PINK1 pathogenesis, we used the Drosophila Pink1 knockout (KO) model. In mitochondria isolated from Pink1-KO flies, mitochondrial respiration driven by the electron transport chain (ETC) is significantly reduced. This reduction is the result of a decrease in ETC complex I and IV enzymatic activity. As a consequence, Pink1-KO flies also display a reduced mitochondrial ATP synthesis. Because mitochondrial dynamics is important for mitochondrial function and Pink1-KO flies have defects in mitochondrial fission, we explored whether fission machinery deficits underlie the bioenergetic defect in Pink1-KO flies. We found that the bioenergetic defects in the Pink1-KO can be ameliorated by expression of Drp1, a key molecule in mitochondrial fission. Further investigation of the ETC complex integrity in wild type, Pink1-KO, PInk1-KO/Drp1 transgenic, or Drp1 transgenic flies indicates that the reduced ETC complex activity is likely derived from a defect in the ETC complex assembly, which can be partially rescued by increasing mitochondrial fission. Taken together, these results suggest a unique pathogenic mechanism of PINK1 PD: The loss of PINK1 impairs mitochondrial fission, which causes defective assembly of the ETC complexes, leading to abnormal bioenergetics.pathology | mitochondrial movement A mple evidence indicates that mitochondrial dysfunction plays a pivotal role in the development of Parkinson's disease (PD) (1-6). A 30-40% reduction of mitochondrial electron transport chain (ETC) complex I activity was observed in the postmortem brains of idiopathic PD patients (7-11). 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone, inhibitors of ETC complex I, induce clinical and pathological manifestations that recapitulate cardinal PD symptoms in humans and in animal models (4,(12)(13)(14)(15)(16), supporting the hypothesis that mitochondrial bioenergetic defects contribute to PD pathogenesis.The significance of mitochondrial dysfunction in the development of PD was further strengthened by the discovery of PINK1 as the causal gene of PARK6. PINK1 encodes a mitochondrial kinase (17), but its physiological role remains to be elucidated. Reduction or loss of PINK1 causes bioenergetic deficits that include loss of membrane potential, calcium buffering, ATP synthesis rate, and respiration in cell culture systems (18-21). In Drosophila and mouse PINK1-KOs, decreased ETC complex I mediated respiration and ATP content have been reported (22)(23)(24).ETC complex assembly depends on inner mitochondrial membrane integrity, which is maintained by fusion and fission processes. Fusion and fission regulate the number, size, and morphology of mitochondria in a dynamic manner, and perturbing these processes could affect membrane stability (25). Several key molecules that regulate these delicate processes have been identified: Dynamin-like GTPase (D...

Parkinson’s disease (PD), the second most common neurodegenerative disorder, is etiologically heterogeneous, with most cases thought to arise from a combination of environmental factors and genetic predisposition; about 10% of cases are caused by single gene mutations. While neurotoxin models replicate many of the key behavioral and neurological features, they often have limited relevance to human exposures. Genetic models replicate known disease-causing mutations, but are mostly unsuccessful in reproducing major features of PD. In this study, we created a BAC (bacterial artificial chromosome) transgenic rat model of PD expressing the E46K mutation of α-synuclein, which is pathogenic in humans. The mutant protein was expressed at levels ~2–3-fold above endogenous α-synuclein levels. At 12 months of age, there was no overt damage to the nigrostriatal dopamine system; however, (i) alterations in striatal neurotransmitter metabolism, (ii) accumulation and aggregation of α-synuclein in nigral dopamine neurons, and (iii) evidence of oxidative stress suggest this model replicates several preclinical features of PD. Further, when these animals were exposed to rotenone, a mitochondrial toxin linked to PD, they showed heightened sensitivity, indicating that α-synuclein expression modulates the vulnerability to mitochondrial impairment. We conclude that these animals are well-suited to examination of gene-environment interactions that are relevant to PD.

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