Nucleotide exchange factors Fes1 and HspBP1 mimic substrate to release misfolded proteins from Hsp70.

Protein quality control depends on the tight regulation of interactions between molecular chaperones and polypeptide substrates. Substrate release from the chaperone Hsp70 is triggered by nucleotide-exchange factors (NEFs) that control folding and degradation fates via poorly understood mechanisms. We found that the armadillo-type NEFs budding yeast Fes1 and its human homolog HspBP1 employ flexible N-terminal release domains (RDs) with substrate-mimicking properties to ensure the efficient release of persistent substrates from Hsp70. The RD contacts the substrate-binding domain of the chaperone, competes with peptide substrate for binding and is essential for proper function in yeast and mammalian cells. Thus, the armadillo domain engages Hsp70 to trigger nucleotide exchange, whereas the RD safeguards the release of substrates. Our findings provide fundamental mechanistic insight into the functional specialization of Hsp70 NEFs and have implications for the understanding of proteostasis-related disorders, including Marinesco-Sjögren syndrome.

Have cranio-vertebral junction anomalies been overlooked as a cause of vertebro-basilar insufficiency?

STUDY DESIGN: A prospective controlled study using single photon emission computed tomography (SPECT) to assess cerebellar perfusion in a cohort of 19 patients with congenital cranio-vertebral junction (CVJ) anomalies, with or without vertebro-basilar insufficiency (VBI). OBJECTIVE: To correlate symptoms of VBI with the presence of posterior circulation ischemia in patients with congenital CVJ anomalies, using technetium 99m ethylene cystine dimer SPECT. SUMMARY OF BACKGROUND DATA: Patients with VBI are rarely investigated for CVJ anomalies, despite the fact that a significant number of patients with congenital CVJ anomalies has VBI. There are also no studies quantifying outcome of surgical interventions, such as like occipito-cervical fusion, in patients with VBI and CVJ anomalies. METHODS: There were 19 consecutive patients with congenital CVJ anomalies who were scheduled for combined transoral odontoidectomy and occipito-cervical fusion were included in the study. Technetium 99m ethylene cystine dimer brain SPECT and clinical assessment of all patients was performed in the preoperative period and at 4 weeks after surgery. Before surgery, patients were divided into 2 groups depending on the clinical findings: (1) symptomatic group, consisting of 12 patients having features suggestive of VBI (drop attacks, episodic vertigo, visual disturbances and dysarthria); and (2) control group, consisting of 7 patients without symptoms of VBI. RESULTS: SPECT showed decreased cerebellar perfusion in 75% (n = 9) of patients in the symptomatic group compared to 14% (n = 1) in the control group before surgery (Fisher exact 2-tailed test, P = 0.019). Following surgery, 8 patients (88.9%) in the symptomatic group and none in the control group had improvement in cerebellar perfusion. Two patients in the symptomatic group who had meningitis develop during the postoperative period had a decrease in cerebellar perfusion on follow-up SPECT. Clinically, all patients with improvement in cerebellar perfusion had improvement in the symptoms of VBI at 1 month of follow-up. CONCLUSIONS: A significant number of patients with congenital CVJ anomalies who have symptoms of VBI develop have decreased cerebellar perfusion shown by SPECT. Rigid internal fixation of the CVJ may alleviate symptoms and improve posterior circulation in some of these patients.

Is medial temporal injury responsible for pediatric postconcussion syndrome? A prospective controlled study with single-photon emission computerized tomography.

OBJECT: The authors sought to correlate the finding of medial temporal hypoperfusion (MTH) demonstrated on single photon emission computerized tomography (SPECT) with pediatric persistent postconcussion syndrome (PPCS) and to ascertain its usefulness in routine clinical practice. METHODS: Thirty consecutive children with minor head injury and features of PPCS underwent SPECT scanning within 72 hours of injury. Those children having MTH on SPECT were included in the test group (14 patients), and the remaining 16 children comprised the control group. At the end of a 3-month period SPECT scanning was repeated and the incidence of PPCS was assessed clinically in both groups. Repeated SPECT scanning at 3 months revealed persisting MTH in 13 children (93%) in the test group; no child developed MTH in the control group. Twelve children were found to have PPCS in the MTH group compared with only two in the control group, and this was highly statistically significant (relative risk 6.86 [95% confidence interval 1.84-25.51], p = 0.0003). CONCLUSIONS: There exists significant MTH in pediatric patients with PPCS, which would imply that medial temporal lobe damage (involving the hippocampus and related structures) may occur after minor head injury and could be responsible for the symptoms of PPCS observed in this group of patients. Brain SPECT scans may thus help in the early identification of children prone to develop PPCS, and serial SPECT scanning may serve as a platform for testing the efficacy of various neurobehavioral and pharmacological interventions in these patients.

Does cerebral perfusion improve following CSF diversion in pediatric hydrocephalus? A prospective study using 99mTc ECD single photon emission computed tomography.

AIMS AND OBJECTIVES: To study regional cerebral perfusion before and after ventriculoperitoneal shunt placement in children with hydrocephalus, using (99m)Tc ECD single photon emission computed tomography (SPECT). MATERIALS AND METHODS: 17 consecutive children (less than 16 years) with hydrocephalus due to various causes, who were planned for ventriculoperitoneal shunt, were included in this prospective study. Brain SPECT using (99m)Tc ECD was performed pre- and postoperatively and changes in cerebral perfusion were compared with the change in ventricular size (assessed using Evan's ratio). OBSERVATIONS: There were 11 males and 6 females with a median age of 24 months. Nine children were up to 2 years of age and the mean duration of symptoms was 6 months. The cause of hydrocephalus was congenital in 10, secondary to tumor in 5 and as sequelae of infection in 2 children. Fourteen children (82%) showed improvement in cerebral perfusion following shunting. Of these, 12 also had a concomitant decrease in ventricular size postoperatively. RESULTS: On logistic regression analysis, none of the factors analyzed, i.e. age, duration of symptoms, etiology of hydrocephalus and decrease in ventricular size, were found to predict improvement of cerebral perfusion following shunting. CONCLUSIONS: Cerebral perfusion improves in the majority of the children following CSF diversionary procedures, and contrary to the common belief, duration of hydrocephalus and decreased ventricular size do not influence this improvement in cerebral perfusion. SPECT can therefore prove to be a valuable tool for objective assessment of improvement in cerebral perfusion in children with hydrocephalus secondary to various etiologies following surgical or medical interventions.