Thyroid transcription factor 1 expression in sellar tumors: a histogenetic marker?

Pituicytomas are rare low-grade gliomas of the neurohypophysis. Their morphology and variable immunophenotype have led to speculation that they arise from pituicytes. Given the role of thyroid transcription factor 1 (TTF-1) in the developing rodent infundibulum and its expression in the adult rat neurohypophysis, we speculated that TTF-1 would be a marker of human pituicytes. Using immunohistochemistry, we found that TTF-1 is strongly expressed in fetal and adult human pituicytes. A survey of sellar masses demonstrated specific TTF-1 expression in pituicytomas (n = 3), atypical pituicytomas (n = 2), and granular cell tumors (n = 4), indicating a common pituicyte lineage. TTF-1 expression in spindle cell oncocytomas (n = 8) is less easily explained but invites speculation. Our observations may have implications for the classification of these rare sellar neoplasms, all the while acknowledging the morphological diversity of pituicyte-related neoplasms.

Primary diffuse leptomeningeal gliomatosis mimicking a chronic inflammatory meningitis.

Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare, fatal, neoplastic condition of infiltrating glial cells into the meninges without evidence of primary tumor in the brain or spinal cord parenchyma. Primary diffuse leptomeningeal gliomatosis often presents with symptoms and physical findings of chronic inflammatory meningitis and raised intracranial pressure, and lacks specific clinical, radiologic, and diagnostic criteria. We report a case of PDLG diagnosed post-mortem, highlighting the diagnostic difficulty in identifying PDLG as the cause of chronic meningitis, even when a neoplastic etiology is suspected. Because multiple cytologies and even a leptomeningeal biopsy did not reveal the diagnosis ante-mortem, we emphasize the consideration of multi-site or repeat leptomeningeal biopsy when a persistent inflammatory infiltrate is found and neurological symptoms are progressive.

Supranuclear vertical gaze abnormalities in sporadic Creutzfeldt-Jakob disease.

Supranuclear gaze palsies are an uncommon feature of Creutzfeldt-Jakob disease (CJD). Most reported cases of CJD with features of supranuclear gaze palsy are familial. We report 2 patients with supranuclear vertical gaze abnormalities associated with spongiform changes in the midbrain. Both patients were found to have sporadic CJD after genetic testing. Distinguishing familial from sporadic CJD in this setting has important genetic and epidemiological implications.

Fragmentation of the Golgi apparatus in neurodegenerative diseases and cell death.

Fragmentation of the neuronal Golgi apparatus (GA) was reported in amyotrophic lateral sclerosis (ALS), corticobasal degeneration, Alzheimer's and Creutzfeldt-Jacob disease, and in spinocerebelar ataxia type 2 (SCA2). In transgenic mice expressing the G93A mutant of Cu/Zn superoxide dismutase (SOD1) of familial ALS (fALS), fragmentation of the GA of spinal cord motor neurons and aggregation of mutant protein were detected months before the onset of paralysis. Moreover, cells that expressed the G93A and G85R mutants of SOD1 showed fragmentation of the GA and decreased viability without apoptosis. We summarize here mechanisms involved in Golgi fragmentation implicating: (a) the dysregulation by mutant SOD1of the microtubule-destabilizing protein Stathmin, (b) the disruption by mutant SOD1of the neuronal cytoplasmic dynein, (c) the coprecipitation of mutant SOD1 with Hsp25 and Hsp27, (d) the reduction of detyrosinated microtubules by aggregated tau which resulted in non-apoptotic cell death and (e) the disruption by mutant growth hormone of the trafficking from the rough endoplasmic reticulum to the GA. The data indicate that neuronal Golgi fragmentation is an early and probably irreversible lesion in neurodegeneration, caused by a variety of mechanisms. Golgi fragmentation is not secondary to apoptosis but it may "trigger" apoptosis.

Dysregulation of stathmin, a microtubule-destabilizing protein, and up-regulation of Hsp25, Hsp27, and the antioxidant peroxiredoxin 6 in a mouse model of familial amyotrophic lateral sclerosis.

Gain-of-function mutations of the Cu/Zn superoxide dismutase (SOD1) gene cause dominantly inherited familial amyotrophic lateral sclerosis. The identification of differentially regulated proteins in spinal cords of paralyzed mice expressing SOD1(G93A) may contribute to understanding mechanisms of toxicity by mutant SOD1. Protein profiling showed dysregulation of Stathmin with a marked decrease of its most acidic and phosphorylated isoform, and up-regulation of heat shock proteins 25 and 27, peroxiredoxin 6, phosphatidylinositol transfer protein-alpha, apolipoprotein E, and ferritin heavy chain. Stathmin accumulated in the cytoplasm of 30% of spinal cord motor neurons with fragmented Golgi apparatus. Overexpression of Stathmin in HeLa cells was associated with collapse of microtubule networks and Golgi fragmentation. These results, together with the decrease of one Stathmin isoform, suggest a role of the protein in Golgi fragmentation. Mutant SOD1 co-precipitated and co-localized with Hsp25 in neurons and astrocytes. Mutant SOD1 may thus deprive cells of the anti-apoptotic and other protective activities of Hsp25. Astrocytes contained peroxiredoxin 6, a unique nonredundant antioxidant. The up-regulation of peroxiredoxin 6 probably constitutes a defense to oxidative stress induced by SOD1(G93A). Direct effects of SOD1(G93A) or sequential reactions triggered by the mutant may cause the protein changes.

Identification of MG-160, a FGF binding medial Golgi sialoglycoprotein, in brain tumors: an index of malignancy in astrocytomas.

Malignant astrocytomas are highly invasive, vascular neoplasms that comprise the majority of nervous system tumors in humans. A strong association has previously been made between malignancy in human astrocytic tumors and increased expression of certain fibroblast growth factor (FGF) family members. MG-160 is an intrinsic type I cysteine-rich membrane sialoglycoprotein that resides in the medial cisternae of the Golgi apparatus, highly homologous to CFR, chicken fibroblast growth factor receptor, and ESL-1, E-selectin ligand. MG-160 binds fibroblast growth factors (FGFs) and may be involved in the intracellular trafficking of FGFs and the regulation of cellular response to FGFs. In the present study MG-160 expression was evaluated in human brain tumors exhibiting varying degrees of malignancy. At the mRNA level MG-160 expression was inversely correlated with the histological grade of astrocytomas such that high levels of MG-160 were observed in low-grade astrocytomas and low levels in malignant astrocytomas. This differential expression of MG-160 mRNA was verified at the protein level using immunohistochemistry. Grade II astrocytomas displayed consistent and intense staining for MG-160 as seen in normal brain. In contrast to the lower grade tumors, grade IV astrocytomas exhibited variable and weaker expression of MG-160. Our results suggest that, MG-160 may participate in malignant progression in astrocytomas. In addition, other brain tumors and human astrocytoma cell lines were characterized for MG-160 expression.

Masses of phosphorylated neurofilaments are associated with abnormal golgi apparatus of anterior horn neurons of beta, beta'-iminodipropionitrile-intoxicated rats.

The Golgi apparatus (GA) of anterior horn neurons of rats chronically intoxicated with beta,beta'-iminodipropionitrile (IDPN) in drinking water was examined with an organelle-specific antibody. The neuropile of the anterior horns contained the typical axonal spheroids associated with IDPN toxicity while the perikarya of approximately one-third of the neurons contained phosphorylated neurofilaments, which are not found in the perikarya of control rat neurons. By serial or double immunostaining with the SMI-31 and anti-MG 160 antibodies, there were no morphological changes of the GA in the majority of neurons including neurons with a mild to moderate degree of neurofilamentous accumulation. However, a few neurons with a massive accumulation of phosphorylated neurofilaments contained abnormal profiles of the GA which consisted of focal clustering, reduction in size and fragmentation. The results suggest that masses of phosphorylated neurofilaments are associated with structural abnormalities of the GA.

Pathology of the inferior olivary nucleus in patients with multiple system atrophy.

The inferior olivary nucleus (ION) from nine patients with multiple system atrophy was examined with antibodies against alpha-synuclein, ubiquitin, synaptophysin, glial fibrillary acidic protein, the Golgi apparatus (GA)-trans-Golgi network (TGN), and microglia/macrophages. As previously reported, there were neuronal loss, gliosis, and alpha-synuclein-positive cytoplasmic inclusions in neurons and glia. In addition, all neurons with alpha-synuclein-positive cytoplasmic inclusions contained abnormal profiles of the GA and TGN, which were reduced in size and numbers. This finding suggests a relationship between the pathogenetic mechanisms causing inclusion body formation and abnormalities of the GA-TGN. This study is also consistent with the conclusion that lesions of the ION may not always reflect changes of transsynaptic degeneration secondary to Purkinje cell loss.

The Golgi apparatus is fragmented in spinal cord motor neurons of amyotrophic lateral sclerosis with basophilic inclusions.

The mechanisms of neuronal death in amyotrophic lateral sclerosis (ALS) are not known. A pathological aggregation of cytoplasmic constituents in the form of variety of inclusions may play a role in the pathogenesis of neuronal death. Cytoplasmic basophilic inclusions (BIs) in motor neurons are commonly found in sporadic juvenile ALS. The functional significance of these inclusions is not known, i.e., whether they represent a protective reaction for the isolation of abnormal products from the cytoplasm, or a sign of irreversible neuronal damage. To gain insights on the significance of BIs we asked whether neurons with BIs had an intact or fragmented Golgi apparatus (GA), a sign of neuronal degeneration reported not only in sporadic and familial ALS with mutations of the Cu/Zn superoxide dismutase gene (SOD1), but also in transgenic mice expressing the G93A mutation of SOD1. In these mice fragmentation of the GA of spinal cord motor neurons was found months before the onset of paralysis. We report here that all neurons bearing the inclusions showed fragmentation and reduced number of GA. These results suggest that common pathogenetic mechanisms are involved in the production of BIs and in the fragmentation of the GA.