تويت
The human nervous system is the organ of consciousness, cognition, ethics, and behavior; as such, it is the most intricate structure known to exist. One-third of the 35,000 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 (Chap. 62). More than 350 different disease-causing genes have now been identified, and >1000 neurologic disorders have been genetically mapped to various chromosomal locations. 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 -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 great optimism that complex genetic disorders, caused by combinations of both genetic and environmental factors, have now become tractable problems. The development of new genetic approaches, such as haplotype mapping for the efficient screening of variants genome-wide along with advances in high-throughput sequencing, are beginning to delineate incompletely penetrant genetic variants that influence susceptibility to, or modify the expression of, complex diseases including age-related macular degeneration, type 2 diabetes mellitus, and Alzheimer's disease.
Not all genetic diseases of the nervous system are caused by simple changes in the linear nucleotide sequence of genes. As the complex architecture of the human genome becomes better defined, many disorders that result from alterations in copy numbers of genes ("gene-dosage" effects) resulting from unequal crossing-over are likely to be identified. The first copy-number disorders to be recognized were Charcot-Marie-Tooth disease type 1A (CMT1A), caused by a duplication in the gene encoding the myelin protein PMP22, and the reciprocal deletion of the gene causing hereditary liability to pressure palsies (HNPP) (Chap. 379). Gene-dosage effects are causative in some cases of Parkinson's disease (-synuclein), Alzheimer's disease (amyloid precursor protein), spinal muscular atrophy (survival motor neuron 2), the dysmyelinating disorder Pelizaeus-Merzbacher syndrome (proteolipid protein 1), late-onset leukodystrophy (lamin B1), and a variety of developmental neurologic disorders. It is now evident that copy-number variations contribute substantially to normal human genomic variation for numerous genes involved in neurologic function, regulation of cell growth, and regulation of metabolism. It is also likely that gene-dosage effects will influence many behavioral phenotypes, learning disorders, and autism spectrum disorders.
The role of splicing variation as a contributor to neurologic disease is another area of active investigation. Alternative splicing refers to the inclusion of different combinations of exons in mature mRNA, resulting in the potential for many different protein products encoded by a single gene. Alternative splicing represents a powerful mechanism for generation of complexity and variation, and this mechanism appears to be highly prevalent in the nervous system, affecting key processes such as neurotransmitter receptors and ion channels. Numerous diseases are already known to result from abnormalities in alternative splicing. Increased inclusion of exon 10-containing transcripts of MAPT can cause frontotemporal dementia. Aberrant splicing also contributes to the pathogenesis of Duchenne, myotonic, and fascioscapulohumeral muscular dystrophies; ataxia telangiectasia; neurofibromatosis; some inherited ataxias; and fragile X syndrome; among other disorders. It is also likely that subtle variations of splicing will influence many genetically complex disorders. Recently a splicing variant of the interleukin 7 receptor chain, resulting in production of more soluble and less membrane-bound receptor, was found to be associated with susceptibility to multiple sclerosis (MS) in multiple different populations.
Epigenetics refers to the mechanisms by which levels of gene expression can be exquisitely modulated, not by variations in the primary genetic sequence of DNA but rather by postgenomic alterations in DNA and chromatin structure, which influence how, when, and where genes are expressed. DNA methylation, as well as methylation and acetylation of histone proteins that interact with nuclear DNA to form chromatin, are key mediators of these events. Epigenetic processes appear to be dynamically active even in postmitotic neurons. Imprinting refers to an epigenetic feature, present for a subset of genes, in which the predominant expression of one allele is determined by its parent-of-origin. The distinctive neurodevelopmental disorders Prader-Willi syndrome (mild mental retardation and endocrine abnormalities) and Angelman syndrome (cortical atrophy, cerebellar dysmyelination, Purkinje cell loss) are classic examples of imprinting disorders whose distinctive features are determined by whether the paternal or maternal copy of chromosome of the critical genetic region 15q11-13 was responsible. Preferential allelic expression, whether due to imprinting, resistance to X-inactivation, or other mechanisms, is likely to play a major role in determining complex behaviors and susceptibility to many neurologic and psychiatric disorders.
The human nervous system is the organ of consciousness, cognition, ethics, and behavior; as such, it is the most intricate structure known to exist. One-third of the 35,000 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 (Chap. 62). More than 350 different disease-causing genes have now been identified, and >1000 neurologic disorders have been genetically mapped to various chromosomal locations. 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 -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 great optimism that complex genetic disorders, caused by combinations of both genetic and environmental factors, have now become tractable problems. The development of new genetic approaches, such as haplotype mapping for the efficient screening of variants genome-wide along with advances in high-throughput sequencing, are beginning to delineate incompletely penetrant genetic variants that influence susceptibility to, or modify the expression of, complex diseases including age-related macular degeneration, type 2 diabetes mellitus, and Alzheimer's disease.
Not all genetic diseases of the nervous system are caused by simple changes in the linear nucleotide sequence of genes. As the complex architecture of the human genome becomes better defined, many disorders that result from alterations in copy numbers of genes ("gene-dosage" effects) resulting from unequal crossing-over are likely to be identified. The first copy-number disorders to be recognized were Charcot-Marie-Tooth disease type 1A (CMT1A), caused by a duplication in the gene encoding the myelin protein PMP22, and the reciprocal deletion of the gene causing hereditary liability to pressure palsies (HNPP) (Chap. 379). Gene-dosage effects are causative in some cases of Parkinson's disease (-synuclein), Alzheimer's disease (amyloid precursor protein), spinal muscular atrophy (survival motor neuron 2), the dysmyelinating disorder Pelizaeus-Merzbacher syndrome (proteolipid protein 1), late-onset leukodystrophy (lamin B1), and a variety of developmental neurologic disorders. It is now evident that copy-number variations contribute substantially to normal human genomic variation for numerous genes involved in neurologic function, regulation of cell growth, and regulation of metabolism. It is also likely that gene-dosage effects will influence many behavioral phenotypes, learning disorders, and autism spectrum disorders.
The role of splicing variation as a contributor to neurologic disease is another area of active investigation. Alternative splicing refers to the inclusion of different combinations of exons in mature mRNA, resulting in the potential for many different protein products encoded by a single gene. Alternative splicing represents a powerful mechanism for generation of complexity and variation, and this mechanism appears to be highly prevalent in the nervous system, affecting key processes such as neurotransmitter receptors and ion channels. Numerous diseases are already known to result from abnormalities in alternative splicing. Increased inclusion of exon 10-containing transcripts of MAPT can cause frontotemporal dementia. Aberrant splicing also contributes to the pathogenesis of Duchenne, myotonic, and fascioscapulohumeral muscular dystrophies; ataxia telangiectasia; neurofibromatosis; some inherited ataxias; and fragile X syndrome; among other disorders. It is also likely that subtle variations of splicing will influence many genetically complex disorders. Recently a splicing variant of the interleukin 7 receptor chain, resulting in production of more soluble and less membrane-bound receptor, was found to be associated with susceptibility to multiple sclerosis (MS) in multiple different populations.
Epigenetics refers to the mechanisms by which levels of gene expression can be exquisitely modulated, not by variations in the primary genetic sequence of DNA but rather by postgenomic alterations in DNA and chromatin structure, which influence how, when, and where genes are expressed. DNA methylation, as well as methylation and acetylation of histone proteins that interact with nuclear DNA to form chromatin, are key mediators of these events. Epigenetic processes appear to be dynamically active even in postmitotic neurons. Imprinting refers to an epigenetic feature, present for a subset of genes, in which the predominant expression of one allele is determined by its parent-of-origin. The distinctive neurodevelopmental disorders Prader-Willi syndrome (mild mental retardation and endocrine abnormalities) and Angelman syndrome (cortical atrophy, cerebellar dysmyelination, Purkinje cell loss) are classic examples of imprinting disorders whose distinctive features are determined by whether the paternal or maternal copy of chromosome of the critical genetic region 15q11-13 was responsible. Preferential allelic expression, whether due to imprinting, resistance to X-inactivation, or other mechanisms, is likely to play a major role in determining complex behaviors and susceptibility to many neurologic and psychiatric disorders.
The human nervous system is the organ of consciousness, cognition, ethics, and behavior; as such, it is the most intricate structure known to exist. One-third of the 35,000 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 (Chap. 62). More than 350 different disease-causing genes have now been identified, and >1000 neurologic disorders have been genetically mapped to various chromosomal locations. 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 -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 great optimism that complex genetic disorders, caused by combinations of both genetic and environmental factors, have now become tractable problems. The development of new genetic approaches, such as haplotype mapping for the efficient screening of variants genome-wide along with advances in high-throughput sequencing, are beginning to delineate incompletely penetrant genetic variants that influence susceptibility to, or modify the expression of, complex diseases including age-related macular degeneration, type 2 diabetes mellitus, and Alzheimer's disease.
Not all genetic diseases of the nervous system are caused by simple changes in the linear nucleotide sequence of genes. As the complex architecture of the human genome becomes better defined, many disorders that result from alterations in copy numbers of genes ("gene-dosage" effects) resulting from unequal crossing-over are likely to be identified. The first copy-number disorders to be recognized were Charcot-Marie-Tooth disease type 1A (CMT1A), caused by a duplication in the gene encoding the myelin protein PMP22, and the reciprocal deletion of the gene causing hereditary liability to pressure palsies (HNPP) (Chap. 379). Gene-dosage effects are causative in some cases of Parkinson's disease (-synuclein), Alzheimer's disease (amyloid precursor protein), spinal muscular atrophy (survival motor neuron 2), the dysmyelinating disorder Pelizaeus-Merzbacher syndrome (proteolipid protein 1), late-onset leukodystrophy (lamin B1), and a variety of developmental neurologic disorders. It is now evident that copy-number variations contribute substantially to normal human genomic variation for numerous genes involved in neurologic function, regulation of cell growth, and regulation of metabolism. It is also likely that gene-dosage effects will influence many behavioral phenotypes, learning disorders, and autism spectrum disorders.
The role of splicing variation as a contributor to neurologic disease is another area of active investigation. Alternative splicing refers to the inclusion of different combinations of exons in mature mRNA, resulting in the potential for many different protein products encoded by a single gene. Alternative splicing represents a powerful mechanism for generation of complexity and variation, and this mechanism appears to be highly prevalent in the nervous system, affecting key processes such as neurotransmitter receptors and ion channels. Numerous diseases are already known to result from abnormalities in alternative splicing. Increased inclusion of exon 10-containing transcripts of MAPT can cause frontotemporal dementia. Aberrant splicing also contributes to the pathogenesis of Duchenne, myotonic, and fascioscapulohumeral muscular dystrophies; ataxia telangiectasia; neurofibromatosis; some inherited ataxias; and fragile X syndrome; among other disorders. It is also likely that subtle variations of splicing will influence many genetically complex disorders. Recently a splicing variant of the interleukin 7 receptor chain, resulting in production of more soluble and less membrane-bound receptor, was found to be associated with susceptibility to multiple sclerosis (MS) in multiple different populations.
Epigenetics refers to the mechanisms by which levels of gene expression can be exquisitely modulated, not by variations in the primary genetic sequence of DNA but rather by postgenomic alterations in DNA and chromatin structure, which influence how, when, and where genes are expressed. DNA methylation, as well as methylation and acetylation of histone proteins that interact with nuclear DNA to form chromatin, are key mediators of these events. Epigenetic processes appear to be dynamically active even in postmitotic neurons. Imprinting refers to an epigenetic feature, present for a subset of genes, in which the predominant expression of one allele is determined by its parent-of-origin. The distinctive neurodevelopmental disorders Prader-Willi syndrome (mild mental retardation and endocrine abnormalities) and Angelman syndrome (cortical atrophy, cerebellar dysmyelination, Purkinje cell loss) are classic examples of imprinting disorders whose distinctive features are determined by whether the paternal or maternal copy of chromosome of the critical genetic region 15q11-13 was responsible. Preferential allelic expression, whether due to imprinting, resistance to X-inactivation, or other mechanisms, is likely to play a major role in determining complex behaviors and susceptibility to many neurologic and psychiatric disorders.
Neurogenetics
The landscape of neurology has been transformed by modern molecular genetics (Chap. 62). More than 350 different disease-causing genes have now been identified, and >1000 neurologic disorders have been genetically mapped to various chromosomal locations. 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 -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 great optimism that complex genetic disorders, caused by combinations of both genetic and environmental factors, have now become tractable problems. The development of new genetic approaches, such as haplotype mapping for the efficient screening of variants genome-wide along with advances in high-throughput sequencing, are beginning to delineate incompletely penetrant genetic variants that influence susceptibility to, or modify the expression of, complex diseases including age-related macular degeneration, type 2 diabetes mellitus, and Alzheimer's disease.
Not all genetic diseases of the nervous system are caused by simple changes in the linear nucleotide sequence of genes. As the complex architecture of the human genome becomes better defined, many disorders that result from alterations in copy numbers of genes ("gene-dosage" effects) resulting from unequal crossing-over are likely to be identified. The first copy-number disorders to be recognized were Charcot-Marie-Tooth disease type 1A (CMT1A), caused by a duplication in the gene encoding the myelin protein PMP22, and the reciprocal deletion of the gene causing hereditary liability to pressure palsies (HNPP) (Chap. 379). Gene-dosage effects are causative in some cases of Parkinson's disease (-synuclein), Alzheimer's disease (amyloid precursor protein), spinal muscular atrophy (survival motor neuron 2), the dysmyelinating disorder Pelizaeus-Merzbacher syndrome (proteolipid protein 1), late-onset leukodystrophy (lamin B1), and a variety of developmental neurologic disorders. It is now evident that copy-number variations contribute substantially to normal human genomic variation for numerous genes involved in neurologic function, regulation of cell growth, and regulation of metabolism. It is also likely that gene-dosage effects will influence many behavioral phenotypes, learning disorders, and autism spectrum disorders.
The role of splicing variation as a contributor to neurologic disease is another area of active investigation. Alternative splicing refers to the inclusion of different combinations of exons in mature mRNA, resulting in the potential for many different protein products encoded by a single gene. Alternative splicing represents a powerful mechanism for generation of complexity and variation, and this mechanism appears to be highly prevalent in the nervous system, affecting key processes such as neurotransmitter receptors and ion channels. Numerous diseases are already known to result from abnormalities in alternative splicing. Increased inclusion of exon 10-containing transcripts of MAPT can cause frontotemporal dementia. Aberrant splicing also contributes to the pathogenesis of Duchenne, myotonic, and fascioscapulohumeral muscular dystrophies; ataxia telangiectasia; neurofibromatosis; some inherited ataxias; and fragile X syndrome; among other disorders. It is also likely that subtle variations of splicing will influence many genetically complex disorders. Recently a splicing variant of the interleukin 7 receptor chain, resulting in production of more soluble and less membrane-bound receptor, was found to be associated with susceptibility to multiple sclerosis (MS) in multiple different populations.
Epigenetics refers to the mechanisms by which levels of gene expression can be exquisitely modulated, not by variations in the primary genetic sequence of DNA but rather by postgenomic alterations in DNA and chromatin structure, which influence how, when, and where genes are expressed. DNA methylation, as well as methylation and acetylation of histone proteins that interact with nuclear DNA to form chromatin, are key mediators of these events. Epigenetic processes appear to be dynamically active even in postmitotic neurons. Imprinting refers to an epigenetic feature, present for a subset of genes, in which the predominant expression of one allele is determined by its parent-of-origin. The distinctive neurodevelopmental disorders Prader-Willi syndrome (mild mental retardation and endocrine abnormalities) and Angelman syndrome (cortical atrophy, cerebellar dysmyelination, Purkinje cell loss) are classic examples of imprinting disorders whose distinctive features are determined by whether the paternal or maternal copy of chromosome of the critical genetic region 15q11-13 was responsible. Preferential allelic expression, whether due to imprinting, resistance to X-inactivation, or other mechanisms, is likely to play a major role in determining complex behaviors and susceptibility to many neurologic and psychiatric disorders.
The human nervous system is the organ of consciousness, cognition, ethics, and behavior; as such, it is the most intricate structure known to exist. One-third of the 35,000 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 (Chap. 62). More than 350 different disease-causing genes have now been identified, and >1000 neurologic disorders have been genetically mapped to various chromosomal locations. 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 -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 great optimism that complex genetic disorders, caused by combinations of both genetic and environmental factors, have now become tractable problems. The development of new genetic approaches, such as haplotype mapping for the efficient screening of variants genome-wide along with advances in high-throughput sequencing, are beginning to delineate incompletely penetrant genetic variants that influence susceptibility to, or modify the expression of, complex diseases including age-related macular degeneration, type 2 diabetes mellitus, and Alzheimer's disease.
Not all genetic diseases of the nervous system are caused by simple changes in the linear nucleotide sequence of genes. As the complex architecture of the human genome becomes better defined, many disorders that result from alterations in copy numbers of genes ("gene-dosage" effects) resulting from unequal crossing-over are likely to be identified. The first copy-number disorders to be recognized were Charcot-Marie-Tooth disease type 1A (CMT1A), caused by a duplication in the gene encoding the myelin protein PMP22, and the reciprocal deletion of the gene causing hereditary liability to pressure palsies (HNPP) (Chap. 379). Gene-dosage effects are causative in some cases of Parkinson's disease (-synuclein), Alzheimer's disease (amyloid precursor protein), spinal muscular atrophy (survival motor neuron 2), the dysmyelinating disorder Pelizaeus-Merzbacher syndrome (proteolipid protein 1), late-onset leukodystrophy (lamin B1), and a variety of developmental neurologic disorders. It is now evident that copy-number variations contribute substantially to normal human genomic variation for numerous genes involved in neurologic function, regulation of cell growth, and regulation of metabolism. It is also likely that gene-dosage effects will influence many behavioral phenotypes, learning disorders, and autism spectrum disorders.
The role of splicing variation as a contributor to neurologic disease is another area of active investigation. Alternative splicing refers to the inclusion of different combinations of exons in mature mRNA, resulting in the potential for many different protein products encoded by a single gene. Alternative splicing represents a powerful mechanism for generation of complexity and variation, and this mechanism appears to be highly prevalent in the nervous system, affecting key processes such as neurotransmitter receptors and ion channels. Numerous diseases are already known to result from abnormalities in alternative splicing. Increased inclusion of exon 10-containing transcripts of MAPT can cause frontotemporal dementia. Aberrant splicing also contributes to the pathogenesis of Duchenne, myotonic, and fascioscapulohumeral muscular dystrophies; ataxia telangiectasia; neurofibromatosis; some inherited ataxias; and fragile X syndrome; among other disorders. It is also likely that subtle variations of splicing will influence many genetically complex disorders. Recently a splicing variant of the interleukin 7 receptor chain, resulting in production of more soluble and less membrane-bound receptor, was found to be associated with susceptibility to multiple sclerosis (MS) in multiple different populations.
Epigenetics refers to the mechanisms by which levels of gene expression can be exquisitely modulated, not by variations in the primary genetic sequence of DNA but rather by postgenomic alterations in DNA and chromatin structure, which influence how, when, and where genes are expressed. DNA methylation, as well as methylation and acetylation of histone proteins that interact with nuclear DNA to form chromatin, are key mediators of these events. Epigenetic processes appear to be dynamically active even in postmitotic neurons. Imprinting refers to an epigenetic feature, present for a subset of genes, in which the predominant expression of one allele is determined by its parent-of-origin. The distinctive neurodevelopmental disorders Prader-Willi syndrome (mild mental retardation and endocrine abnormalities) and Angelman syndrome (cortical atrophy, cerebellar dysmyelination, Purkinje cell loss) are classic examples of imprinting disorders whose distinctive features are determined by whether the paternal or maternal copy of chromosome of the critical genetic region 15q11-13 was responsible. Preferential allelic expression, whether due to imprinting, resistance to X-inactivation, or other mechanisms, is likely to play a major role in determining complex behaviors and susceptibility to many neurologic and psychiatric disorders.
The human nervous system is the organ of consciousness, cognition, ethics, and behavior; as such, it is the most intricate structure known to exist. One-third of the 35,000 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 (Chap. 62). More than 350 different disease-causing genes have now been identified, and >1000 neurologic disorders have been genetically mapped to various chromosomal locations. 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 -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 great optimism that complex genetic disorders, caused by combinations of both genetic and environmental factors, have now become tractable problems. The development of new genetic approaches, such as haplotype mapping for the efficient screening of variants genome-wide along with advances in high-throughput sequencing, are beginning to delineate incompletely penetrant genetic variants that influence susceptibility to, or modify the expression of, complex diseases including age-related macular degeneration, type 2 diabetes mellitus, and Alzheimer's disease.
Not all genetic diseases of the nervous system are caused by simple changes in the linear nucleotide sequence of genes. As the complex architecture of the human genome becomes better defined, many disorders that result from alterations in copy numbers of genes ("gene-dosage" effects) resulting from unequal crossing-over are likely to be identified. The first copy-number disorders to be recognized were Charcot-Marie-Tooth disease type 1A (CMT1A), caused by a duplication in the gene encoding the myelin protein PMP22, and the reciprocal deletion of the gene causing hereditary liability to pressure palsies (HNPP) (Chap. 379). Gene-dosage effects are causative in some cases of Parkinson's disease (-synuclein), Alzheimer's disease (amyloid precursor protein), spinal muscular atrophy (survival motor neuron 2), the dysmyelinating disorder Pelizaeus-Merzbacher syndrome (proteolipid protein 1), late-onset leukodystrophy (lamin B1), and a variety of developmental neurologic disorders. It is now evident that copy-number variations contribute substantially to normal human genomic variation for numerous genes involved in neurologic function, regulation of cell growth, and regulation of metabolism. It is also likely that gene-dosage effects will influence many behavioral phenotypes, learning disorders, and autism spectrum disorders.
The role of splicing variation as a contributor to neurologic disease is another area of active investigation. Alternative splicing refers to the inclusion of different combinations of exons in mature mRNA, resulting in the potential for many different protein products encoded by a single gene. Alternative splicing represents a powerful mechanism for generation of complexity and variation, and this mechanism appears to be highly prevalent in the nervous system, affecting key processes such as neurotransmitter receptors and ion channels. Numerous diseases are already known to result from abnormalities in alternative splicing. Increased inclusion of exon 10-containing transcripts of MAPT can cause frontotemporal dementia. Aberrant splicing also contributes to the pathogenesis of Duchenne, myotonic, and fascioscapulohumeral muscular dystrophies; ataxia telangiectasia; neurofibromatosis; some inherited ataxias; and fragile X syndrome; among other disorders. It is also likely that subtle variations of splicing will influence many genetically complex disorders. Recently a splicing variant of the interleukin 7 receptor chain, resulting in production of more soluble and less membrane-bound receptor, was found to be associated with susceptibility to multiple sclerosis (MS) in multiple different populations.
Epigenetics refers to the mechanisms by which levels of gene expression can be exquisitely modulated, not by variations in the primary genetic sequence of DNA but rather by postgenomic alterations in DNA and chromatin structure, which influence how, when, and where genes are expressed. DNA methylation, as well as methylation and acetylation of histone proteins that interact with nuclear DNA to form chromatin, are key mediators of these events. Epigenetic processes appear to be dynamically active even in postmitotic neurons. Imprinting refers to an epigenetic feature, present for a subset of genes, in which the predominant expression of one allele is determined by its parent-of-origin. The distinctive neurodevelopmental disorders Prader-Willi syndrome (mild mental retardation and endocrine abnormalities) and Angelman syndrome (cortical atrophy, cerebellar dysmyelination, Purkinje cell loss) are classic examples of imprinting disorders whose distinctive features are determined by whether the paternal or maternal copy of chromosome of the critical genetic region 15q11-13 was responsible. Preferential allelic expression, whether due to imprinting, resistance to X-inactivation, or other mechanisms, is likely to play a major role in determining complex behaviors and susceptibility to many neurologic and psychiatric disorders.
تعليق