I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

Principles of Neural Science

Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

Post-transcriptional gene regulation (PTGR) concerns processes involved in the maturation, transport, stability and translation of coding and non-coding RNAs. RNA-binding proteins (RBPs) and ribonucleoproteins coordinate RNA processing and PTGR. The introduction of large-scale quantitative methods, such as next-generation sequencing and modern protein mass spectrometry, has renewed interest in the investigation of PTGR and the protein factors involved at a systems-biology level. Here, we present a census of 1,542 manually curated RBPs that we have analysed for their interactions with different classes of RNA, their evolutionary conservation, their abundance and their tissue-specific expression. Our analysis is a critical step towards the comprehensive characterization of proteins involved in human RNA metabolism.

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A census of human RNA-binding proteins.

The discovery that expansion of unstable repeats can cause a variety of neurological disorders has changed the landscape of disease-oriented research for several forms of mental retardation, Huntington disease, inherited ataxias, and muscular dystrophy. The dynamic nature of these mutations provided an explanation for the variable phenotype expressivity within a family. Beyond diagnosis and genetic counseling, the benefits from studying these disorders have been noted in both neurobiology and cell biology. Examples include insight about the role of translational control in synaptic plasticity, the role of RNA processing in the integrity of muscle and neuronal function, the importance of Fe-S-containing enzymes for cellular energy, and the dramatic effects of altering protein conformations on neuronal function and survival. It is exciting that within a span of 15 years, pathogenesis studies of this class of disorders are beginning to reveal pathways that are potential therapeutic targets.

Trinucleotide Repeat Disorders

The pathobiology of vascular dementia

Multiple system atrophy (MSA) is a well-known neurodegenerative disorders that present parkinsonism syndrome and autonomic dysfunction. Patients with MSA who have the combination of parkinsonism and cerebellar ataxia are referred to as MSA-C. Brain diffusion-weighted imaging (DWI) offers the potential for objective criteria in the diagnosis of MSA. We aim to develop an automatic method to segment out the abnormal whole brain area in MSA-C patients based on the 13-direction DWI raw data. The whole brain DWI raw data of fifteen normal subjects and nine MSA-C patients were analyzed. In this study, we proposed a novel method to perform tissue segmentation directly based on the directional information of the DWI images, rather than using the parametric images, such as fractional anisotropy (FA) and apparent diffusion coefficient (ADC) as in the previous literatures. Specifically, a hierarchical clustering (HC) technique was first applied on the down-sampled data to initialize the model parameters for each tissue cluster followed by automatic segmentation using the expectation maximization (EM) algorithm. Our results demonstrate that the HC-EM is effective in multi-tissue classification, namely, the cerebrospinal fluid, gray matter, and several areas of white matters, on the DWI raw data. The segmented patterns and the corresponding intensities of thirteen directions of the cerebellum in MSA-C patients showed the decrease of the anisotropy, which were evidently different from the results in normal subjects.

Multi-tissue Classification of Diffusion-Weighted Brain Images in Multiple System Atrophy Using Expectation Maximization Algorithm Initialized by Hierarchical Clustering

Background Uncertainty in diagnosing Huntington's disease (HD) may occur in the absence of a family history or typical movement disorders. HD is characterized by a progressive disturbance of typical movement disorders (i.e., chorea, athetosis), psychiatric symptoms (i.e., depression, insomnia, anxiety, suspiciousness), and cognitive deterioration, in the absence of a dominant family history of similar disorders. Often, some of these symptoms are missing, which makes the diagnosis difficult. In recent years molecular testing has become the gold standard for diagnosing HD. Diagnostic accuracy for HD on genetic screening of patients and their families is important. We evaluated a polymerase chain reaction (PCR) technique for the detection of CAG trinucleotide repeats in the Huntington IT15 gene on chromosome 4 for the diagnosis of HD. Methods A segment of the Huntington gene was amplified by PCR using the primers HD-1 and HD-3 flanking the CAG repeat sequence. Genomic PCR was performed on DNA extracted from the peripheral leukocytes of 12 patients from three unrelated families. One family had no documented history of movement or mental disorders, while the other two did. These two, therefore, required pre-symptomatic testing and exclusion of diagnosis in a seemingly symptomatic case. Results We successfully identified four subjects with expansion of CAG trinucleotide repeats in Huntington gene IT15 on chromosome 4. Movement disorder was present in three of these subjects. One was the sister of subject 4, who was asymptomatic. A sister of subject 9 was ruled out from having HD by PCR despite having depression symptoms, which are frequently seen in HD patients. Conclusions Genetic testing is of prime importance in the establishment of an accurate diagnosis of Huntington's disease, especially in "sporadic" cases and presymptomatic family members, and for the exclusion of HD in family members with equivocal symptoms.

Usefulness of molecular testing in Huntington's disease.

a fi rst-line medicine. However, abnormal regulation of AMPK has been implicated in several neurodegenerative diseases, including Alzheimer ’ s disease, Parkinson ’ s disease, Huntington ’ s disease, and amyotrophic lateral sclerosis. Liu and Chern (2015) review the recent studies that have delineated the functions of AMPK and outline a body of evidence for AMPK ’ s potential to be an eff ective target in the development of therapeutics for the neurodegenerative diseases in our aging society. TDP-43 is a multifunctional RNA/DNA-binding protein that is well-conserved across many species from mammals to Drosophila . It is also a major component of the hallmark pathological inclusions associated with degenerating motor neurons in ALS. Further, TDP-43 is a signature protein in a frontotemporal lobar degeneration subtype. Given the lack of eff ective treatment for these neurodegenerative diseases, Cheng et al. (2015) describe the generation and characterization of a new Drosophila model of ALS-TDP with transgenic expression of the fl y ortholog of TDP-43, dTDP. They are able to bypass the deleterious eff ect of dTDP during development by targeting only the adult fl y with the control of a temperaturesensitive, motor neuron-specifi c expression driver. Overexpression of dTDP leads to a shortened life span and impaired locomotor activities of fl ies. To counter the defects in this fl y model of ALS-TDP, Cheng et al. demonstrate the therapeutic eff ects of the autophagy activator rapamycin. Administration of rapamycin before the induction of dTDP overexpression could signifi cantly reduce dTDP (  ) aggregates as well as partially alleviate the shortened life span and locomotive defects of these ALS-TDP fl ies. Furthermore, they identifi ed S6K, a downstream mediator of the target of rapamycin (TOR) pathway, as one genetic modifi er of dTDP. The data further suggest that autophagy activators, for example, rapamycin, are promising therapeutic molecules to retard the progression of neurodegenerative diseases with TDP-43 proteinopathies. This new fl y model of ALS-TDP with temporal and spatial control can facilitate the screening and validation of therapeutic drugs for ALS.

Neurodegenerative diseases: From the bench to the clinic

[This corrects the article DOI: 10.1371/journal.pone.0187503.].

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Bing-Wen Soong

Papers

Multi-tissue Classification of Diffusion-Weighted Brain Images in Multiple System Atrophy Using Expectation Maximization Algorithm Initialized by Hierarchical Clustering

Usefulness of molecular testing in Huntington's disease.

Neurodegenerative diseases: From the bench to the clinic

Correction: Mutational analysis of ITPR1 in a Taiwanese cohort with cerebellar ataxias.