https://www.normalesup.org/~vorgogoz/articles/D.pachea-references/alternative-splicing/Stamm2005-alternative-splicing-review.pdf

Function of alternative splicing.

Meningiomas account for up to 30% of all primary intracranial tumours. They are histologically classified according to the World Health Organization (WHO) classification of tumours of the nervous system. Most meningiomas are benign lesions of WHO grade I, whereas some meningioma variants correspond with WHO grades II and III and are associated with a higher risk of recurrence and shorter survival times. Mutations in the NF2 gene and loss of chromosome 22q are the most common genetic alterations associated with the initiation of meningiomas. With increase in tumour grade, additional progression-associated molecular aberrations can be found; however, most of the relevant genes are yet to be identified. High-throughput techniques of global genome and transcriptome analyses and new meningioma models provide increasing insight into meningioma biology and will help to identify common pathogenic pathways that may be targeted by new therapeutic approaches.

/pdf/histological-classification-and-molecular-genetics-of-vo08tp63pl.pdf

Histological classification and molecular genetics of meningiomas.

PDZ domains are abundant protein interaction modules that often recognize short amino acid motifs at the C-termini of target proteins. They regulate multiple biological processes such as transport, ion channel signaling, and other signal transduction systems. This review discusses the structural characterization of PDZ domains and the use of recently emerging technologies such as proteomic arrays and peptide libraries to study the binding properties of PDZ-mediated interactions. Regulatory mechanisms responsible for PDZ-mediated interactions, such as phosphorylation in the PDZ ligands or PDZ domains, are also discussed. A better understanding of PDZ protein-protein interaction networks and regulatory mechanisms will improve our knowledge of many cellular and biological processes.

/pdf/pdz-domains-and-their-binding-partners-structure-specificity-3auau47bl8.pdf

PDZ domains and their binding partners: structure, specificity, and modification

Meningiomas are extremely common adult brain tumors originating from meningeal coverings of the brain and spinal cord. While most are slowly growing Word Health organization (WHO) grade I tumors, rare variants (clear cell, chordoid, papillary, and rhabdoid), as well as brain invasive (WHO grade II), atypical (WHO grade II), and anaplastic (WHO grade III) meningiomas are considerably more aggressive. This review summarizes the histopathological and genetic features of meningiomas, including differential diagnosis, pitfalls, and grading challenges. Early stages of meningioma tumorigenesis are closely linked to inactivation of one or more members of the 4.1 superfamily, including the neurofibromatosis type 2 (NF2) and 4.1B (DAL-1) genes, which interact with the 14-3-3 protein family. Other chromosome 22q genes implicated include BAM22, BCR (breakpoint cluster region), and TIMP-1, the last of which is implicated in higher-grade meningiomas. Atypical meningiomas also commonly show chromosomal losses of 1p, 6q, 10, 14q, and 18q, as well as multiple chromosomal gains. While most relevant genes remain unknown, two chromosome 14q candidates (MEG3 and NDRG2) have recently been identified. In addition to alterations of CDKN2A, p14 ARF , and CDKN2B tumor suppressor genes on 9p21, a contribution of the wingless (wnt) pathway with alterations of the E-cadherin and beta-catenin proteins, as well as alterations of the hedgehog signaling pathway have been implicated in anaplastic meningiomas. The integration of histopathological appearance, complex genetic/genomic data, and outcome will likely result in the identification of clinically distinct meningioma subgroups, which in turn can facilitate the development of targeted therapeutic strategies.

Pathological classification and molecular genetics of meningiomas

Bioconjugation is a burgeoning field of research. Novel methods for the mild and site-specific derivatization of proteins, DNA, RNA, and carbohydrates have been developed for applications such as ligand discovery, disease diagnosis, and high-throughput screening. These powerful methods owe their existence to the discovery of chemoselective reactions that enable bioconjugation under physiological conditions—a tremendous achievement of modern organic chemistry. Here, we review recent advances in bioconjugation chemistry. Additionally, we discuss the stability of bioconjugation linkages—an important but often overlooked aspect of the field. We anticipate that this information will help investigators choose optimal linkages for their applications. Moreover, we hope that the noted limitations of existing bioconjugation methods will provide inspiration to modern organic chemists.

/pdf/advances-in-bioconjugation-1h0q2zfmse.pdf

Advances in Bioconjugation.

Schwannomin isoform-1 interacts with syntenin via PDZ domains.

Oculopharyngeal muscular dystrophy is caused by expansion of a (GCG)n trinucleotide repeat in the poly(A) binding protein 2 (PABP2) gene. The pathological hallmark of oculopharyngeal muscular dystrophy is the accumulation of intranuclear inclusions in muscle fibers. To test whether the polyalanine expansion of PABP2 directly leads to the formation of the nuclear aggregates, both normal and expanded PABP2 cDNAs were expressed in COS-7 cells. We find that expression of mutated PABP2 protein is sufficient for its accumulation as intranuclear inclusions.

PABP2 polyalanine tract expansion causes intranuclear inclusions in oculopharyngeal muscular dystrophy.

Autosomal Recessive Cerebellar Ataxias

Increased exonic de novo mutation rate in individuals with SCZ

OPMD Therapy Progress 2 ARC Publishing Introduction Oculopharyngeal muscular dystrophy (OPMD) is a midlife onset (~45 years) primarily autosomal dominant muscular disease with minor neuronal involvement [1]. It is characterized by progressive swallowing difficulties, eyelid drooping and serious proximal limb weakness at later stages. The pathological hallmark of the disease is the presence of intranuclear inclusions (INI) in the muscle biopsies of patients [2, 3]. The highest prevalence of OPMD is in the French-Canadian population, where 1/1,000 people are at risk, though the disease is found worldwide. In 1990, our group began collecting samples from affected families and, in 1998, we identified the poly(A) binding protein nuclear 1 protein (PABPN1) gene as causative [4, 5]. OPMD results from short expansions of a 5’ trinucleotide alanine coding repeat located at the N-terminus end of the protein. The normal PABPN1 protein has 10 alanines and the mutated (expPABPN1) has 11-18 [4]. The PABPN1 protein has 306 amino acids. In addition to the polyalanine stretch, PABPN1 contains a proline-rich region in the N-terminus, an RNA-binding domain in the central region and an arginine-rich C-terminus. PABPN1’s well-recognized role in mRNA polyadenylation and transport is attributed to its ability to bind poly(A) tails with high affinity [6, 7]. A number of recent studies have revealed additional roles for the protein, including transcription regulation and poly(A) RNA export [8, 9]. PABPN1 appears to control gene expression in various tissues, including muscles [10, 11]. The depletion of PABPN1 in mouse primary muscle cells leads to myogenic defects and reduced differentiation [11]. PABPN1 expression in human cells has also been reported to be autoregulated through a mechanism of controlled intron retention coupled to pre-mRNA decay [12]. Moreover, PABPN1 was shown to suppress alternative cleavage, polyadenylation sites [13] and the regulation of long non-coding RNAs (lncRNA) [8]. Since our publication of the first PABPN1 mutations in 1998, a striking array of cellular and molecular mechanisms has been proposed to contribute to the pathogenesis of OPMD (Figure 1). Proposed mechanisms include sequestration of cellular factors by the mutant protein [14, 15], defects in the potential clearance pathway (i.e. chaperones, and ubiquitin-proteasome pathway UPP) [14, 15], alterations in transcription, histone acetylation alteration [16], aging-associated factors [17], Wnt pathway perturbation [18], and aberrant protein-protein interactions [19]. The toxic gain-of-function mechanism of OPMD supports the hypothesis that disease onset and progression is dependent upon the expansion of the polyalanine tract. The mutant protein becomes misfolded due to the presence of expanded tract as it allows a transition toward a distinct β-sheet conformation that may cause toxicity in several ways. It may exert toxicity as a monomer or it may self-associate to form toxic oligomers. The oligomers can assemble into larger aggregated species and ultimately they are deposited in macromolecular intracellular inclusions. The context of the polyalanine tract within the PABPN1 protein has an essential role in the disease process. The composition of regions flanking the repeats can alter the biochemical and biophysical properties of expPABPN1. Differences in the production and/or clearance of expPABPN1 in eyelid and pharyngeal muscles might be determinants of age-related muscle vulnerability in OPMD. These might be used as therapeutic targets. For example, as polyalanine expansions lead to misfolded PABPN1 protein, structural refolding assisted by enhanced chaperone activity might be beneficial. An increased degradation of expPABPN1 and aggregates via proteasomes could reduce the amounts of toxic species inside the cell. Despite our understanding of the normal functions of PABPN1 protein, and the proposed mechanisms contributing to OPMD pathogenesis, the mechanisms whereby mutated expPABPN1 is toxic to muscle is still a mystery. Alanine is a highly hydrophobic amino acid, often found in the cores of proteins [20], and polyalanine oligomers are extremely resistant to chemical denaturation and enzymatic degradation [21]. Our initial hypothesis was that expanded polyalanine tract of expPABPN1 forms β-pleated sheets that give rise to toxic INI. As our work progresses, we are discovering that soluble expPABPN1 may be the most critical species for toxicity [22]. OPMD shares many common features with other polyalanine diseases, polyglutamine diseases, muscle dystrophic diseases, and diseases caused by RNA binding proteins (Figure 2). In addition to OPMD, at least eight other inherited diseases are now caused by genes with polyalanine expansions [23]. All the affected genes in polyalanine diseases, except PABPN1, code for transcription factors that play important roles in early development [23]. OPMD was the first polyalanine disorder identified that leads to INI in muscle nuclei of patients[2]. Later studies demonstrated the presence of protein aggregates in several polyalanine diseases [24-26]. Hydrophobic polyalanine tracts in the normal range are considered to be flexible spacers Figure 1. A model of molecular mechanisms behind OPMD pathology. The indicated pathways point to possible sites for therapeutic intervention.

Patrick A. Dion

Papers

Schwannomin isoform-1 interacts with syntenin via PDZ domains.

PABP2 polyalanine tract expansion causes intranuclear inclusions in oculopharyngeal muscular dystrophy.

Autosomal Recessive Cerebellar Ataxias

Increased exonic de novo mutation rate in individuals with SCZ

Current targeted therapeutic strategies for oculopharyngeal muscular dystrophy: from pharmacological to RNA replacement and gene editing therapies