## INTRODUCTION

The human nervous system is the organ of consciousness, cognition, ethics, and behavior; as such, it is the most intricate structure known to exist. More than one-third of the 23,000 genes encoded in the human genome are expressed in the nervous system. Each mature brain is composed of 100 billion neurons, several million miles of axons and dendrites, and >1015 synapses. Neurons exist within a dense parenchyma of multifunctional glial cells that synthesize myelin, preserve homeostasis, and regulate immune responses. Measured against this background of complexity, the achievements of molecular neuroscience have been extraordinary. This chapter reviews selected themes in neuroscience that provide a context for understanding fundamental mechanisms underlying neurologic disorders.

## NEUROGENETICS

The landscape of neurology has been transformed by modern molecular genetics. Several hundred neurologic and psychiatric disorders can now be diagnosed through genetic testing (http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests). The vast majority of these represent highly penetrant mutations that cause rare neurologic disorders; alternatively, they represent rare monogenic causes of common phenotypes. Examples of the latter include mutations of the amyloid precursor protein in familial Alzheimer’s disease, the microtubule-associated protein tau (MAPT) in frontotemporal dementia, and α-synuclein in Parkinson’s disease. These discoveries have been profoundly important because the mutated gene in the familial disorder often encodes a protein that is also pathogenetically involved (although not mutated) in the typical, sporadic form. The common mechanism involves disordered processing and, ultimately, aggregation of the protein leading to cell death (see “Protein Aggregation and Neurodegeneration,” below).

There is optimism that complex genetic disorders, caused by combinations of both genetic and environmental factors, have now become tractable problems. Genome-wide association studies (GWAS) have been carried out in many complex neurologic disorders, with many hundreds of variants identified, nearly all of which confer only a small increment in disease risk (1.15- to 1.5-fold). GWAS studies are rooted in the “common disease, common variant” hypothesis, as they examine potential risk alleles that are relatively frequent (e.g. >5%) in the general population. More than 1500 GWAS studies have been carried out, with notable successes such as the identification of 110 risk alleles for multiple sclerosis (Chap. 458). Furthermore, using bioinformatics tools, risk variants can be aligned in functional biologic pathways to identify novel pathogenic mechanisms as well as to reveal heterogeneity (e.g., different pathways in different individuals). Despite these successes, many experienced geneticists question the real value of common disease-associated variants, particularly whether they are actually causative or merely mark the approximate locations of more important—truly causative—rare mutations.

This debate has set the stage for the next revolution in human genetics, made possible by the development of increasingly efficient and cost-effective high-throughput sequencing methodologies. It is already possible to sequence an entire human genome in approximately an hour, at a cost of only $1300 for the entire coding sequence (“whole-exome”) or$3000 for the entire genome; it is certain ...

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