Parkinson's disease (PD) is characterized by the selective vulnerability of the nigrostriatal dopaminergic circuit. Recently, loss-offunction mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset PD. How PINK1 deficiency causes dopaminergic dysfunction and degeneration in PD patients is unknown. Here, we investigate the physiological role of PINK1 in the nigrostriatal dopaminergic circuit through the generation and multidisciplinary analysis of PINK1 ؊/؊ mutant mice. We found that numbers of dopaminergic neurons and levels of striatal dopamine (DA) and DA receptors are unchanged in PINK1 ؊/؊ mice. Amperometric recordings, however, revealed decreases in evoked DA release in striatal slices and reductions in the quantal size and release frequency of catecholamine in dissociated chromaffin cells. Intracellular recordings of striatal medium spiny neurons, the major dopaminergic target, showed specific impairments of corticostriatal long-term potentiation and long-term depression in PINK1 ؊/؊ mice. Consistent with a decrease in evoked DA release, these striatal plasticity impairments could be rescued by either DA receptor agonists or agents that increase DA release, such as amphetamine or L-dopa. These results reveal a critical role for PINK1 in DA release and striatal synaptic plasticity in the nigrostriatal circuit and suggest that altered dopaminergic physiology may be a pathogenic precursor to nigrostriatal degeneration.neurodegeneration ͉ Parkinson's disease ͉ substantia nigra P arkinson's disease (PD) is the most common movement disorder and is characterized by bradykinesia, rigidity, resting tremor, and postural instability. These clinical features are thought to result from reduced dopaminergic input to the striatum and the loss of dopaminergic neurons in the pars compacta of the substantia nigra (SNpc). Although the occurrence of PD is largely sporadic, mutations in five distinct genes have been linked to clinical syndromes that are often indistinguishable from sporadic PD. Of these, mutations in the parkin, DJ-1, and PINK1 (PTEN induced kinase 1) genes are recessively inherited and include large exonic deletions or frame-shift truncations, suggesting a loss-of-function pathogenic mechanism (1-3).PINK1 was originally identified as a gene whose transcription was activated by the tumor suppressor PTEN in carcinoma cell lines (4). The PINK1 gene has eight exons spanning 1.8 kb and encodes 581 aa residues. The deduced amino acid sequence indicates that PINK1 contains a mitochondrial targeting motif (amino acids 1-34) and a kinase domain (amino acids 156-509) that is highly homologous to Ca 2ϩ /calmodulin-dependent kinases. Since the first report linking recessively inherited nonsense (W437X) and missense (G309D) mutations in PINK1 to familial PARK6 cases (3), large numbers (Ͼ30) of additional truncation and missense mutations have been identified in early-onset PD cases with or without family history (5-11). Genetic analysis revealed that homozygous and compound heterozygous mutatio...

Loss-of-function mutations in DJ-1 cause a subset of familial Parkinson disease (PD). However, the mechanism underlying the selective vulnerability in dopaminergic pathway due to the inactivation of DJ-1 is unclear. Previously, we have reported that DJ-1 is a neuroprotective transcriptional coactivator interacting with the transcriptional co-repressor pyrimidine tract-binding protein-associated splicing factor (PSF). Here we show that DJ-1 and PSF bind and regulate the human tyrosine hydroxylase (TH) promoter. Inactivation of DJ-1 by small interference RNA (siRNA) results in decreased TH expression and L-DOPA production in human dopaminergic cell lines. Consistent with its role as a transcriptional regulator, DJ-1 specifically suppresses the global SUMO-1 modification. High molecular weight sumoylated protein species, including PSF, accumulate in the lymphoblast cells from the patients carrying pathogenic DJ-1 mutations. DJ-1 elevates the TH expression by inhibiting the sumoylation of PSF and preventing its sumoylation-dependent recruitment of histone deacetylase 1. Furthermore, siRNA silencing of DJ-1 decreases the acetylation of TH promoter-bound histones, and histone deacetylase inhibitors restore the DJ-1 siRNA-induced repression of TH. Therefore, our results suggest DJ-1 as a regulator of protein sumoylation and directly link the loss of DJ-1 expression and transcriptional dysfunction to impaired dopamine synthesis. Parkinson disease (PD)4 is a common progressive movement disease characterized by the selective loss of dopaminergic neurons and the decrease of striatal dopamine levels (1). Dopamine deficiency in PD patients contributes to the typical clinical features, which include tremor, bradykinesia, rigidity, and postural instability. These symptoms can be temporally controlled by administering medications targeting dopamine metabolism and function, such as the dopamine precursor L-DOPA and dopamine agonists. The rate-limiting enzyme for dopamine synthesis is tyrosine hydroxylase (TH).Loss-of-function mutations in the DJ-1 gene cause early-onset Parkinsonism (2), although the disease-causing mechanism remains to be fully resolved. The evolutionarily conserved DJ-1 has been shown to regulate oxidative stress, apoptosis, protein aggregation, and transcription in various subcellular compartments (3-8). In vitro experiments from several laboratories have clearly demonstrated the neuroprotective activity of DJ-1, although different molecular mechanisms have been proposed (4, 7-9). The role of DJ-1 in neuronal survival is strengthened by in vivo studies using Drosophila lacking DJ-1, which exhibit increased sensitivity to oxidative stress or environmental mitochondrial toxins (10, 11). In one study, inactivation of a Drosophila DJ-1 homolog by siRNA leads to the degeneration of the TH-positive dopaminergic neurons as in PD patients (10). On the other hand, DJ-1-deficient mice do not reproduce the typical neuropathology of PD patients, such as the loss of the dopaminergic neurons and the formation of intracellu...

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Transit-oriented development (TOD) has become popular across the nation not just as a partial solution for rampant highway traffic congestion but also as a way of life. The emphasis of TOD on creating a close-knit, pedestrian-friendly, distinctively designed form of urban and suburban development appears able to elicit support even where transit service is minimal or nonexistent. TOD is solidly ensconced as a significant component of smart growth, sustainable development, and new urbanism. Public officials often view the concept as a valuable building block for developing accessible and attractive communities, and transit agencies value its generation of increased ridership. The benefits of TOD for transit operators and broader transportation policies are fairly well established. Less well appreciated is that urban sites most suitable for TODs are transit friendly but often developer unfriendly, since they are often more expensive and more complicated to develop. In contrast, the suburban locations most desired by residents and businesses are developer friendly but transit unfriendly. For them to support transit requires special efforts to increase density, mixed uses, and pedestrian orientation, qualities uncommon and often resisted in the suburbs. A number of projects generally considered among planners and developers to be effective TODs were examined, and their strengths and weaknesses are reviewed from a transit perspective, on the basis of several specific principles. The TOD concept is demonstrated to be alive and well and evolving toward the described ideals.

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Building on a 19-region study of transit-focused development, some directions are suggested for evolving development opportunities associated with the light rail transit systems built and planned in recent decades. Transportation and land use planners continue to propound the concept of transit-focused development that can increase use of transit systems, reduce dependency on automobiles, create desirable living and working environments, and help to meet environmental goals. In their expectations of achieving a substantial amount of transit-focused development, however, planners must recognize the realities of the real estate markets, public policy trends, and the nature of rail lines themselves. Especially along the light rail lines that provide service in many regions, development opportunities will be influenced by changes in the development industry and its primary markets, increasing deference to neighborhood and community groups in decision making regarding development, and the generally lower intensity of use of suburban rail stations compared with many stations along heavy rail lines. Successful development around light rail stations, as with heavy rail systems, will require a timely confluence of market demand with supportive public policies and actions. Unlike experience with heavy rail systems, however, noncentral-business-district stations on light rail lines are more likely to attract relatively small, uncomplicated projects. Transit agencies and local governments will be required to invest more time and energy in nurturing these kinds of projects.