The mitochondrial toxin 3-nitropropionic acid induces differential expression patterns of apoptosis-related markers in rat striatum

The mitochondrial toxin 3-nitropropionic acid (3-NP) causes selective striatal lesions in rats and serves as an experimental model for the neurodegenerative disorder Huntington's disease (HD). Apoptotic cell death has been implicated for the neuronal degeneration that occurs in HD brains. The present study was designed to investigate whether the 3-NP-induced cell death in rats involves apoptosis and an altered expression of Bcl-2 family proteins. Systemic administration of 3-NP via subcutaneous Alzet pumps resulted in lesions of variable severity with neuronal loss and gliosis in the striatum. Using the terminal transferase-mediated biotinylated-UTP nick end-labelling (TUNEL) of DNA, TUNEL-positive cells exhibiting typical apoptotic morphology were detected only in the striatum of rats with a severe lesion. Furthermore, the neuronal expression of the pro-apoptotic protein Bax was strongly increased in the core of the severe lesion. Expression of the anti-apoptotic marker Bcl-2 was unchanged in this location, but was enhanced in the margins of the lesions. A moderately increased expression of both Bax and Bcl-2 was observed in dark neurones in the mild lesion and in the subtle lesion. The presence of nuclear DNA fragmentation, strong granular Bax expression and an increased Bax/Bcl-2 ratio in the centre of severe lesions suggests the occurrence of apoptotic cell death following 3-NP administration. In contrast, the dark compromised neurones observed in 3-NP-treated animals revealed an equally enhanced expression of both Bax and Bcl-2, but lacked TUNEL-labelling, and are therefore not apoptotic.     

Dysregulation of dopamine signaling in the dorsal striatum inhibits feeding

Dopamine signaling is an important component of many goal-directed behaviors, such as feeding. Acute disruption of dopamine signaling using pharmacological agents tends to inhibit normal feeding behaviors in rodents. Likewise, genetically engineered dopamine-deficient (DD) mice are unable to initiate sufficient feeding and will starve by approximately 3 weeks of age if untreated. Adequate feeding by DD mice can be achieved by daily administration of L-3,4-dihydroxyphenylalanine (L-dopa), a precursor of dopamine, which can be taken up by dopaminergic neurons, converted to dopamine, and released in a regulated manner. In contrast, adequate feeding cannot be restored with apomorphine (APO), a mixed agonist that activates D1 and D2 receptors. Viral restoration of dopamine production in neurons that project to the dorsal striatum also restores feeding in DD mice. Administration of amphetamine (AMPH) or nomifensine (NOM), drugs which increase synaptic dopamine concentration, inhibits food intake in virally rescued DD mice (vrDD) as in control animals. These results indicate that the dysregulation of dopamine signaling in the dorsal striatum is sufficient to induce hypophagia and suggest that regulated release of dopamine in that brain region is essential for normal feeding and, probably, many other goal-directed behaviors.     

Evidence for genetic heterogeneity in D‐2‐hydroxyglutaric aciduria

We performed molecular, enzyme, and metabolic studies in 50 patients with D ‐2‐hydroxyglutaric aciduria (D ‐2‐HGA) who accumulated D ‐2‐hydroxyglutarate (D ‐2‐HG) in physiological fluids. Presumed pathogenic mutations were detected in 24 of 50 patients in the D ‐2‐hydroxyglutarate dehydrogenase (D2HGDH) gene, which encodes D ‐2‐hydroxyglutarate dehydrogenase (D ‐2‐HGDH). Enzyme assay of D ‐2‐HGDH confirmed that all patients with mutations had impaired enzyme activity, whereas patients with D ‐2‐HGA whose enzyme activity was normal did not have mutations. Significantly lower D ‐2‐HG concentrations in body fluids were observed in mutation‐positive D ‐2‐HGA patients than in mutation‐negative patients. These results imply that multiple genetic loci may be associated with hyperexcretion of D ‐2‐HG. Accordingly, we suggest a new classification: D ‐2‐HGA Type I associates with D ‐2‐HGDH deficiency, whereas idiopathic D ‐2‐HGA manifests with normal D ‐2‐HGDH activity and higher D ‐2‐HG levels in body fluids compared with Type I patients. It remains possible that several classifications for idiopathic D ‐2‐HGA patients with diverse genetic loci will be revealed in future studies. Hum Mutat 31:1–5, 2010. © 2009 Wiley‐Liss, Inc.     

Dispositional optimism and the risk of depressive symptoms during 15 years of follow-up: the Zutphen Elderly Study

OBJECTIVE: It is unclear whether the personality trait of dispositional optimism, defined in terms of generalized positive outcome expectancies, life engagement, and a future orientation, has a protective effect on the development of depression in community-dwelling elderly men. METHODS: We included 464 men aged 64 to 84 years (mean 70.8; SD 4.6) with complete data at baseline and at 5 years of follow-up in a prospective cohort study with a follow-up period of 15 years. In 1985, 1990, 1995 and 2000 dispositional optimism was assessed using a 4-item questionnaire, and in 1990, 1995 and 2000 depressive symptoms were assessed by the Zung self-rating depression scale (SDS). Logistic regression was used to estimate odds ratios for the development of depressive symptoms (i.e., Zung SDS > or = 50). RESULTS: The cumulative incidence for depressive symptoms was 44% (n = 202) after 15 years follow-up. Dispositional optimism predicted for a lower cumulative incidence of depressive symptoms with an odds ratio of 0.23 (95% confidence interval 0.15-0.36; high vs. low optimism). The protective effect remained unaffected after multivariate adjustment for age, self-rated health, cardiovascular disease, education, and physical activity. In men free of depressive symptoms in 1990, the protective effect of dispositional optimism persisted. LIMITATION: The dispositional optimism scale has not been validated against the 'Life Orientation Test'. CONCLUSIONS: Dispositional optimism protects against the development of depressive symptoms during 15 years of follow-up in elderly community-dwelling men.     

Mutations in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss

In two large Turkish consanguineous families, a locus for autosomal recessive nonsyndromic hearing loss (ARNSHL) was mapped to chromosome 6p21.3 by genome-wide linkage analysis in an interval overlapping with the loci DFNB53 (COL11A2), DFNB66, and DFNB67. Fine mapping excluded DFNB53 and subsequently homozygous mutations were identified in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene, also named tetraspan membrane protein of hair cell stereocilia (TMHS) gene, which was recently shown to be mutated in the "hurry scurry" mouse and in two DFNB67-linked families from Pakistan. In one family, we found a homozygous one-base pair deletion, c.649delG (p.Glu216ArgfsX26) and in the other family we identified a homozygous transition c.494C>T (p.Thr165Met). Further screening of index patients from 96 Turkish ARNSHL families and 90 Dutch ARNSHL patients identified one additional Turkish family carrying the c.649delG mutation. Haplotype analysis revealed that the c.649delG mutation was located on a common haplotype in both families. Mutation screening of the LHFPL5 homologs LHFPL3 and LHFPL4 did not reveal any disease causing mutation. Our findings indicate that LHFPL5 is essential for normal function of the human cochlea.