Hypothalamic neurons that express neuropeptide Y (NPY) and agouti-related protein (AgRP) are thought to be critical regulators of feeding behavior and body weight. To determine whether NPY/AgRP neurons are essential in mice, we targeted the human diphtheria toxin receptor to the Agrp locus, which allows temporally controlled ablation of NPY/AgRP neurons to occur after an injection of diphtheria toxin. Neonatal ablation of NPY/AgRP neurons had minimal effects on feeding, whereas their ablation in adults caused rapid starvation. These results suggest that network-based compensatory mechanisms can develop after the ablation of NPY/AgRP neurons in neonates but do not readily occur when these neurons become essential in adults.

Mutations in the human parkin gene cause autosomal recessive juvenile parkinsonism, a heritable form of Parkinson's disease (PD). To determine whether mutations in the mouse parkin gene (Park2) also result in a parkinsonian phenotype, we generated mice with a targeted deletion of parkin exon 2. Using an extensive behavioral screen, we evaluated neurological function, motor ability, emotionality, learning, and memory in aged Parkin-deficient mice. The behavioral profile of Parkin-deficient mice on a B6;129S4 genetic background was strikingly similar to that of control mice, and most differences were not reproducible by using coisogenic mice on a 129S4 genetic background. Moreover, catecholamine levels in the striatum, olfactory bulb, and spinal cord of Parkin-deficient mice were normal. In contrast to previous studies using independently generated Parkin-deficient mice, we found no evidence for nigrostriatal, cognitive, or noradrenergic dysfunction. Understanding why Parkin-deficient mice do not exhibit robust signs of parkinsonism could advance knowledge and treatment of PD.mouse behavior ͉ dopamine ͉ norepinephrine ͉ gene knockout ͉ Parkinson P arkinson's disease (PD) is a devastating neurodegenerative disorder that affects Ͼ500,000 people in the United States alone (1). The age-related and progressive signs of PD classically include resting tremor, muscular rigidity, abnormal gait, and slow movement; however, other signs and symptoms associated with parkinsonism can include somatosensory deficits, impaired cognitive function, and psychiatric disturbances (2-4). Many PD signs result from the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Dopamine replacement medications often succeed in managing parkinsonism; however, these treatments lose effectiveness, have undesirable effects, and do not prevent the underlying neurodegeneration. Understanding the molecular mechanism of dopaminergic neuron degeneration would facilitate the development of therapies that prevent PD.The identification of mutations in single genes that result in familial parkinsonism will help advance our understanding of the molecular mechanism of PD. Mutations in the human parkin gene are responsible for autosomal recessive juvenile parkinsonism (AR-JP), a heritable disease that resembles PD (5). The Parkin protein is a widely expressed, E3 ubiquitin-protein ligase that is thought to target specific proteins for proteasomal degradation (5-7). Presumably, in the absence of Parkin function, these protein targets accumulate to toxic levels and cause dopamine neuron degeneration.To investigate how mutations in parkin lead to parkinsonism, we generated mice with a targeted disruption of Park2. We hypothesized that Parkin-deficient mice would recapitulate the behavioral signs and pathology of AR-JP. During our investigation, several other groups independently generated and described mice with various targeted deletions of the parkin gene (8-11); however, results from these studies have raised many new issues. First, the b...

Sequestration of misfolded proteins into pericentriolar inclusions called aggresomes is a means that cells use to minimize misfolded protein-induced cytotoxicity. However, the molecular mechanism by which misfolded proteins are recruited to aggresomes remains unclear. Mutations in the E3 ligase parkin cause autosomal recessive Parkinson's disease that is devoid of Lewy bodies, which are similar to aggresomes. Here, we report that parkin cooperates with heterodimeric E2 enzyme UbcH13/Uev1a to mediate K63-linked polyubiquitination of misfolded DJ-1. K63-linked polyubiquitination of misfolded DJ-1 serves as a signal for interaction with histone deacetylase 6, an adaptor protein that binds the dynein–dynactin complex. Through this interaction, misfolded DJ-1 is linked to the dynein motor and transported to aggresomes. Furthermore, fibroblasts lacking parkin display deficits in targeting misfolded DJ-1 to aggresomes. Our findings reveal a signaling role for K63-linked polyubiquitination in dynein-mediated transport, identify parkin as a key regulator in the recruitment of misfolded DJ-1 to aggresomes, and have important implications regarding the biogenesis of Lewy bodies.