Mutant LRRK2 enhances glutamatergic synapse activity and evokes excitotoxic dendrite degeneration.
Biochimica et biophysica acta
2014; 1842 (9): 1596-1603
Tectal pineal cyst in a 1-year-old girl
2014; 45 (3): 653-656
Mutations in leucine-rich repeat kinase 2 (LRRK2), which are associated with autosomal dominant Parkinson's disease, elicit progressive dendrite degeneration in neurons. We hypothesized that synaptic dysregulation contributes to mutant LRRK2-induced dendritic injury. We performed in vitro whole-cell voltage clamp studies of glutamatergic receptor agonist responses and glutamatergic synaptic activity in cultured rat cortical neurons expressing full-length wild-type and mutant forms of LRRK2. Expression of the pathogenic G2019S or R1441C LRRK2 mutants resulted in larger whole-cell current responses to direct application of AMPA and NMDA receptor agonists. In addition, mutant LRRK2-expressing neurons exhibited an increased frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs) in conjunction with increased excitatory synapse density as assessed by immunofluorescence for PSD95 and VGLUT1. Mutant LRRK2-expressing neurons showed enhanced vulnerability to acute synaptic glutamate stress. Furthermore, treatment with the NMDA receptor antagonist memantine significantly protected against subsequent losses in dendrite length and branching complexity. These data demonstrate an early association between mutant LRRK2 and increased excitatory synapse activity, implicating an excitotoxic contribution to mutant LRRK2 induced dendrite degeneration.
View details for DOI 10.1016/j.bbadis.2014.05.016
View details for PubMedID 24874075
Co-occurrence of a cerebral cavernous malformation and an orbital cavernous hemangioma in a patient with seizures and visual symptoms: Rare crossroads for vascular malformations.
Surgical neurology international
2014; 5: S148-54
Glial cysts of the pineal gland can frequently be found in adults and children, but only rarely do they enlarge to become clinically relevant. We report a unique presentation of a pineal cyst in the midbrain tectum of a 16-month-old girl who initially presented with ptosis and strabismus. Preoperative imaging studies and intraoperative findings revealed no continuity between the tectal cyst and the pineal gland proper. We surmise that this tectal pineal cyst may have arisen from duplicated pineal gland tissue.
View details for DOI 10.1016/j.humpath.2013.10.002
View details for Web of Science ID 000331854400028
GA binding protein augments autophagy via transcriptional activation of BECN1-PIK3C3 complex genes.
2014; 10 (9)
Cerebral cavernous malformations (CCMs) are angiographically occult vascular malformations of the central nervous system. As a result of hemorrhage and mass effect, patients may present with focal neurologic deficits, seizures, and other symptoms necessitating treatment. Once symptomatic, most often from hemorrhage, CCMs are treated with microsurgical resection. Orbital cavernous hemangiomas (OCHs) are similar but distinct vascular malformations that present within the orbital cavity. Even though CCMs and OCHs are both marked by dilated endothelial-lined vascular channels, they are infrequently seen in the same patient.We provide a brief overview of the two related pathologies in the context of a patient presenting to our care with concomitant lesions, which were both resected in full without complication.This is the first known report that describes a case of concomitant CCM and OCH and explores the origins of two pathologies that are rarely encountered together in neurosurgical practice. Recognition of disparate symptomatologies is important for properly managing these patients.
View details for DOI 10.4103/2152-7806.134810
View details for PubMedID 25071938
Occult pigmented ganglioglioma in an adult male with chronic posttraumatic epilepsy.
2013; 32 (3): 192-195
Macroautophagy is a vesicular catabolic trafficking pathway that is thought to protect cells from diverse stressors and to promote longevity. Recent studies have revealed that transcription factors play important roles in the regulation of autophagy. In this study, we have identified GA binding protein (GABP) as a transcriptional regulator of the combinatorial expression of BECN1-PIK3C3 complex genes involved in autophagosome initiation. We performed bioinformatics analyses that demonstrated highly conserved putative GABP sites in genes that encode BECN1/Beclin 1, several BECN1 interacting proteins, and downstream autophagy proteins including the ATG12-ATG5-ATG16L1 complex. We demonstrate that GABP binds to the promoter regions of BECN1-PIK3C3 complex genes and activates their transcriptional activities. Knockdown of GABP reduced BECN1-PIK3C3 complex transcripts, BECN1-PIK3C3 complex protein levels and autophagy in cultured cells. Conversely, overexpression of GABP increased autophagy. Nutrient starvation increased GABP-dependent transcriptional activity of BECN1-PIK3C3 complex gene promoters and increased the recruitment of GABP to the BECN1 promoter. Our data reveal a novel function of GABP in the regulation of autophagy via transcriptional activation of the BECN1-PIK3C3 complex.
View details for PubMedID 25046113