Deleterious sustained inflammation mediated by activated microglia is common to most of neurologic disorders. Here, we identified sirtuin 2 (SIRT2), an abundant deacetylase in the brain, as a major inhibitor of microglia‐mediated inflammation and neurotoxicity. SIRT2‐deficient mice (SIRT2−/−) showed morphological changes in microglia and an increase in pro‐inflammatory cytokines upon intracortical injection of lipopolysaccharide (LPS). This response was associated with increased nitrotyrosination and neuronal cell death. Interestingly, manipulation of SIRT2 levels in microglia determined the response to Toll‐like receptor (TLR) activation. SIRT2 overexpression inhibited microglia activation in a process dependent on serine 331 (S331) phosphorylation. Conversely, reduction of SIRT2 in microglia dramatically increased the expression of inflammatory markers, the production of free radicals, and neurotoxicity. Consistent with increased NF‐κB‐dependent transcription of inflammatory genes, NF‐κB was found hyperacetylated in the absence of SIRT2, and became hypoacetylated in the presence of S331A mutant SIRT2. This finding indicates that SIRT2 functions as a ‘gatekeeper’, preventing excessive microglial activation through NF‐κB deacetylation. Our data uncover a novel role for SIRT2 opening new perspectives for therapeutic intervention in neuroinflammatory disorders.

Pituitary tumors are the most common form of intracranial neoplasms. However, clinically relevant pituitary tumors presenting with disturbances of hormonal secretion or mass effect are rare and they only represent about 10 % of all surgically resected intracranial neoplasms. Prolactinomas are the most common types of pituitary adenomas. Generally, hormonal expression patterns provided by immunohistochemistry (IHC) studies are correlated with the clinical features and endocrine activity of the patients. Nonetheless, exceptions occur where the immunocytochemical staining is not concordant with the clinical picture. Pituitary adenomas presenting with apoplexy are well known. However, pituitary adenomas causing cerebral stroke and resulting in hemiplegia are unusual. Here, we report an unusual case of prolactinoma with cerebral stroke and sparse prolactin (PRL) expression. A 25-year-old woman complaining of amenorrhea, dysphasia, and left hemiplegia presented with serum PRL level in excess of 4,700 ng/ml. Pre-operational radiology images revealed a giant macroadenoma and a thalamic infarct due to carotid compression. Transcranial surgery was performed. IHC study of the adenoma revealed no hormonal expression other than sparse PRL immunoreactivity. Therefore, a sparsely granulated PRL cell adenoma was diagnosed. The patient is still under follow-up with continuing cabergoline treatment.

-In the central nervous system (CNS), oligodendrocytes (OLs) ensheath axons with lipid-rich myelin membranes that provide an electrical insulation and are essential for fast nerve impulse transmission. However, myelination is not the only function of OLs, which is important for neurons. The axo-glial interaction is vital for the long-term survival of the axons, independently from myelination. The novel role of OLs in supporting axonal integrity was best exemplified by the findings on mutant mice with the genetic deletion of two structural proteins of the CNS myelin, namely proteolipid protein (PLP) and 2'-3'-cyclic nucleotide phosphodiesterase (CNP1). Lack of these proteins led to an axonopathy in the CNS, despite the absence of major myelin abnormalities. Gel-based proteome analysis performed to explore possible secondary molecular alterations in Plp null myelin revealed that Sirtuin 2 (SIRT2) was the only protein, other than PLP and its splice isoform DM20, to be virtually absent. These findings suggested that the axonal pathology observed in Plp null mice may be at least partially due to the lack of SIRT2.SIRT2 is one of the mammalian orthologs of the silent information regulator 2 (Sir2) protein, which is an nicotinamide adenine dinucleotide (NAD + )-dependent histone deacetylase and is involved in many cellular mechanisms in yeast and worms. SIRT2 has a cytoplasmic distribution, to colocalize with microtubule network and to deacetylate α-tubulin at the lysine-40 residue. SIRT2 is highly expressed in the brain, specifically in oligodendrocytes at early stages of myelination and is incorporated into myelin in presence of PLP/DM20, being localized at the inner and outer loops and the paranodes of the CNS myelin.To identify the role of SIRT2 in the axon protection, we analyzed mice lacking Sirt2 expression. Surprisingly, we found that SIRT2 is dispensable for myelin formation and maintenance, as axons of all calibers in both the central and peripheral nervous system were normally myelinated in the Sirt2 null mice. In addition, these mice showed no apparent CNS axonopathy suggesting that SIRT2 may not be the only key player of the yet unexplained axonoprotective function of PLP.To test the hypothesis that SIRT2 serves as an NAD + -dependent regulator of glial neuroprotection, we did not only use pharmacological approaches to induce axonal stress, but we also generated double mutant mice expressing neuronal and glial disease genes. For example, we found that the axonal degeneration caused by the lack of Cnp1 was dramatically enhanced by the additional absence of Sirt2. As a result, the Sirt2*Cnp1 double null mutant mice displayed increased inflammation, and a significantly reduced lifespan. These findings support the hypothesis that SIRT2 is a myelin-associated sensor for axonal stress that is essential for long-term axonal survival. the cytoplasm of OLs. The compaction of the opposing outer leaflets form the intraperiod lines (IPL), which are interseparating the MDL (courtesy to Dr. Wiebke Möbius, EM Facility, Ma...

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