Alexander Jeans

A dominant mutation in Snap25 causes impaired vesicle trafficking, sensorimotor gating, and ataxia in the blind-drunk mouse.

The neuronal soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is essential for synaptic vesicle exocytosis, but its study has been limited by the neonatal lethality of murine SNARE knockouts. Here, we describe a viable mouse line carrying a mutation in the b-isoform of neuronal SNARE synaptosomal-associated protein of 25 kDa (SNAP-25). The causative I67T missense mutation results in increased binding affinities within the SNARE complex, impaired exocytotic vesicle recycling and granule exocytosis in pancreatic β-cells, and a reduction in the amplitude of evoked cortical excitatory postsynaptic potentials. The mice also display ataxia and impaired sensorimotor gating, a phenotype which has been associated with psychiatric disorders in humans. These studies therefore provide insights into the role of the SNARE complex in both diabetes and psychiatric disease.

Identification of a new Pmp22 mouse mutant and trafficking analysis of a Pmp22 allelic series suggesting that protein aggregates may be protective in Pmp22-associated peripheral neuropathy.

Abstract We have identified and characterized a new peripheral myelin protein 22 (Pmp22) mouse mutant. The mutation results in a serine to threonine amino acid substitution at residue 72, which is a hot spot for mutation in human PMP22, leading to the peripheral neuropathy Dejerine–Sottas syndrome. We have previously described two other Pmp22 mutants, providing an allelic series for gene function analysis. Pmp22 mutations generally lead to abnormal intracellular trafficking of Pmp22, and we show that each mutant protein in the allelic series has a unique pattern of intracellular localization in transfected cell lines. The mutant protein from the less severely affected mutants occurs in large aggregates, while the mutant protein from the most severely affected mutant occurs in a diffuse perinuclear pattern that largely colocalizes with wild-type protein. This suggests that large Pmp22 aggregates may be protective in this form of peripheral neuropathy.

Increased expression of dysbindin-1A leads to a selective deficit in NMDA receptor signaling in the hippocampus

The effects of the major schizophrenia susceptibility gene disease DTNBP1 on disease risk are likely to be mediated through changes in expression level of the gene product, dysbindin-1. How such changes might influence pathogenesis is, however, unclear. One possible mechanism is suggested by recent work establishing a link between altered dysbindin-1 expression and changes in surface levels of N-methyl-d-aspartate receptors (NMDAR), although neither the precise nature of this relationship, nor the mechanism underlying it, are understood. Using organotypic slices of rat hippocampus, we show that increased expression of dysbindin-1A in pyramidal neurons causes a severe and selective hypofunction of NMDARs and blocks induction of LTP. Cell surface, but not cytoplasmic, expression of the NR1 subunit of the NMDAR is decreased, suggesting dysregulation of NMDAR trafficking and, consistent with this, pharmacological inhibition of clathrin-dependent endocytosis is sufficient to reverse the deficit in NMDAR signaling. These results support the idea that the level of the NMDAR at the plasma membrane is modulated by changes in dysbindin-1 expression and offer further insight into the role of dysbindin-1 at an important cellular pathway implicated in schizophrenia.

Is Parkinson’s Disease Truly a Prion-Like Disorder? An Appraisal of Current Evidence

Parkinsons disease (PD) is the worlds second most common neurodegenerative disease and most common movement disorder. Characterised by a loss of dopaminergic neurons and the development of intraneuronal inclusions known as Lewy bodies, it has classically been thought of as a cell-autonomous disease. However, in 2008, two groups reported the startling observation of Lewy bodies within embryonic neuronal grafts transplanted into PD patients little more than a decade previously, suggesting that PD pathology can be propagated to neighbouring cells and calling basic assumptions of our understanding of the disease into question. Subsequent research has largely served to confirm this interpretation, pointing towards a prion-like intercellular transfer of misfolded α-synuclein, the main component of Lewy bodies, as central to PD. This shift in thinking offers a revolutionary approach to PD treatment, potentially enabling a transition from purely symptomatic therapy to direct targeting of the pathology that drives disease progression. In this short review, we appraise current experimental support for PD as a prion-like disease, whilst highlighting areas of controversy or inconsistency which must be resolved. We also offer a brief discussion of the therapeutic implications of these discoveries.

Cerebral primitive neuroectodermal tumor in an adult with a heterozygous MSH2 mutation

Background. A 37-year-old woman presented with a supratentorial cerebral mass, which was diagnosed histologically as a primitive neuroectodermal tumor. She had been treated for rectal adenocarcinoma 7 years previously. A family history revealed a young-onset colorectal carcinoma in the patients father.Investigations. Immunohistochemical analysis for DNA mismatch repair proteins, germline mutation analysis of MSH2.Diagnosis. Lynch syndrome with a heterozygous germline mutation in MSH2.Management. Debulking of the cerebral tumor, craniospinal axis radiotherapy, and genetic counseling of family.

Imaging Synaptic Vesicles Using VGLUT1-Venus Knock-In Mice: Insights into the Dynamic Nature of Intersynaptic Vesicle Exchange

Traditionally, synapses have been regarded as compartmentalized nodes of communication, in which axonal boutons and dendritic spines operate independently of their neighbors and the efficacy of neurotransmission is regulated solely by patterned activity between presynaptic and postsynaptic cells.

Primary angiitis of the CNS mimicking a spinal cord tumour.

JO N 2 85 3 on the right. Deep tendon reflexes were depressed in the legs, and the plantar responses were absent. There was a sensory level to light touch and pin-prick corresponding to spinal segment T12. Vibration sense was absent up to the iliac crest. No abnormality was detected in the arms and cranial nerves. A general medical examination was unremarkable. Magnetic resonance imaging (MRI) of the spinal cord, with and without contrast, showed T2 signal change within the cord from T3 to the conus (Fig. 1). There was mild cord expansion in the lower thoracic region with irregular uptake of contrast. An MRI of the brain was normal. Laboratory investigations for routine biochemistry, full blood count, ESR, C-reactive protein, antinuclear antibodies, ANCA, rheumatoid factor, cryoglobulins, complement, antineuronal antibodies, Hepatitis B and C, syphilis serology and urinalysis were normal or negative. Cerebrospinal fluid showed a mononuclear Dirk Baumer Enrico Flossmann Simon Cudlip Geradine Quaghebeur Alexander Jeans Kevin Talbot

Muscle hemorrhage in a paraplegic adult with neurofibromatosis type 1 and an associated vasculopathy

A vasculopathy associated with neurofibromatosis type 1 (NF1) was first described in1945 [Reubi, 1945], and is now thought to complicate around 10% of cases. Stenotic lesions are the most common, manifesting as cerebral and visceral infarcts, aortic coarctation, and mesenteric ischaemia [Rosser et al., 2005; Oderich et al., 2007]. The vascular abnormalities also predispose to arterio-venous malformations, fistulae and aneurysms, leading to hemorrhage [Siddhartha et al., 2003; White et al., 2004; Bueno et al., 2005; Ishizu et al., 2006], and toulcerationof the skin and gastrointestinal tract [Obermoser et al., 2004]. Macroscopically, marked vascular fragility has been described [Shimizu et al., 1998]. Previous cases of hemorrhage have been reported in association with NF1, but we report a novel case with an unusual clinical presentation. A 35-year-old Caucasian man had a history of involvement in a traffic accident, which required internal fixation of a right femoral fracture and emergency splenectomy for delayed splenic rupture. He developed paraplegia with a sensory level at T10. His pattern of neurological deficit was consistent with disruption to anterior spinal artery supply, and was attributed to severe hypotension from bleeding. Subsequently, routine post-splenectomy prophylaxis with penicillin V was established and he was treated for hypertension. He underwent neurorehabilitation and continued to live an active life, though wheelchair dependent. He was subsequently well for 4 years, until presenting with several days’ history of erythema and swelling of his left thigh.Onexamination, he had marked swelling of the thigh, low-grade fever (37.48C) and tachycardia (110 beats per minute). He was anemic (Hb 9.9 g/dl) and had raised inflammatory markers (WBC 28.9 10/L, neutrophils 23.4 10/L, C-reactive protein (CRP) >285 mg/L). We instituted therapy with intra-venous antibiotics for presumed pyomyositis. MRI demonstrated marked signal change in all muscles of the thigh, compatible with either inflammatory, infectious or atrophic change, and an anterior heterogenous mass with signal characteristics consistent with resolving hematoma. Surgical exploration identified a necrotic hematoma within vastus medialis. Histopathological examination of muscle samples demonstrated hemorrhagic, necrotic muscle containing an acute inflammatory infiltrate, deemed compatible with infection. He had three subsequent hospital admissions over the next 9 months under similar circumstances, including involvement of the contralateral thigh. On each occasion, he had fever (up to 408C), tachycardia (120–130 bpm) and raised inflammatory markers. Blood cultures were negative, but MRI suggested myositis in association with small fluid collections in all compartments of the thigh (Fig. 1a). His clotting profile remained normal throughout, but he presented each time with a thrombocytosis in keeping with an acute inflammatory response. There

The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neurons

Abstract Mutations in the Tre2/Bub2/Cdc16 (TBC)1 domain family member 24 (TBC1D24) gene are associated with a range of inherited neurological disorders, from drug-refractory lethal epileptic encephalopathy and DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures) to non-syndromic hearing loss. TBC1D24 has been implicated in neuronal transmission and maturation, although the molecular function of the gene and the cause of the apparently complex disease spectrum remain unclear. Importantly, heterozygous TBC1D24 mutation carriers have also been reported with seizures, suggesting that haploinsufficiency for TBC1D24 is significant clinically. Here we have systematically investigated an allelic series of disease-associated mutations in neurons alongside a new mouse model to investigate the consequences of TBC1D24 haploinsufficiency to mammalian neurodevelopment and synaptic physiology. The cellular studies reveal that disease-causing mutations that disrupt either of the conserved protein domains in TBC1D24 are implicated in neuronal development and survival and are likely acting as loss-of-function alleles. We then further investigated TBC1D24 haploinsufficiency in vivo and demonstrate that TBC1D24 is also crucial for normal presynaptic function: genetic disruption of Tbc1d24 expression in the mouse leads to an impairment of endocytosis and an enlarged endosomal compartment in neurons with a decrease in spontaneous neurotransmission. These data reveal the essential role for TBC1D24 at the mammalian synapse and help to define common synaptic mechanisms that could underlie the varied effects of TBC1D24 mutations in neurological disease.

Homeostatic Presynaptic Plasticity Is Specifically Regulated by P/Q-type Ca2+ Channels at Mammalian Hippocampal Synapses

Summary Voltage-dependent Ca2+ channels (VGCC) represent the principal source of Ca2+ ions driving evoked neurotransmitter release at presynaptic boutons. In mammals, presynaptic Ca2+ influx is mediated mainly via P/Q-type and N-type VGCC, which differ in their properties. Changes in their relative contributions tune neurotransmission both during development and in Hebbian plasticity. However, whether this represents a functional motif also present in other forms of activity-dependent regulation is unknown. Here, we study the role of VGCC in homeostatic plasticity (HSP) in mammalian hippocampal neurons using optical techniques. We find that changes in evoked Ca2+ currents specifically through P/Q-type, but not N-type, VGCC mediate bidirectional homeostatic regulation of both neurotransmitter release efficacy and the size of the major synaptic vesicle pools. Selective dependence of HSP on P/Q-type VGCC in mammalian terminals has important implications for phenotypes associated with P/Q-type channelopathies, including migraine and epilepsy.