NEURODEGENERATIVE DISEASES

Neurodegenerative diseases represent a diverse spectrum of chronic neurological disorders, of possible genetic etiology, that are associated with the progressive loss of motor, sensory, and perceptual functions and associated cognitive and behavioral deficits. These disorders are characterized by disease-selective profiles of adult-onset neuronal cell loss within areas of the cerebral cortex, basal ganglia, cerebellum, brain stem, and motor systems. The biological underpinnings of these complex clinicopathological entities have remained obscure.

Research on pathological aging has focused mainly on defining the causes of cell death during adult life, and has favored the cumulative cellular-damage hypothesis. However, more recent studies have suggested the existence of a final common pathway for pathological cell death in these disorders. In this scenario, individual environmental stressors that normally do not promote cell death act upon precursors of vulnerable neuronal subpopulations that exist in a precarious abnormal steady state. These observations are compatible with the increasing evidence that neurodegenerative diseases may represent fundamental disorders of neural development, characterized by novel biological responses to subtle developmental abnormalities that alter the cellular homeostasis of neuronal biosynthetic pathways without causing obvious gross developmental deficits.

In support of this developmental model of disease pathogenesis, genes that are mutated in neurodegenerative diseases code for proteins that are expressed throughout the periods of neural induction, patterning of the neural tube, and progressive stages of neurogenesis and neuronal maturation. Numerous molecular genetic studies further suggest that the nonmutated form of these disease genes normally mediate a broad range of fundamental neurodevelopmental events. The protein products of these disease genes can interact with additional protein partners that help to orchestrate many of these essential neural maturational processes.

Additional investigations have shown that pathogenic mutations compromise only a subset of these protein-protein interactions. Further, although transgenic mice harboring pathogenic mutations for human neurodegenerative diseases do not display the obvious deficits in patterning or neurogenesis that are observed with the corresponding gene deletion models, they do exhibit subtle but progressive molecular, physiological, and structural abnormalities that predate the occurrence of a neurological phenotype and evidence of irreversible cellular injury. These pathogenic mutations are also associated with the presence of abnormal profiles of activation of selective cellular genes, and these pathologic events can prevent the proper integration and transmission of neural network signals within vulnerable neuronal subpopulations.

Finally, specific gene alleles that alter the probability of acquiring an individual neurodegenerative disease, or that modify the clinical course of the disease (e.g., apolipoprotein E [ApoE]), can influence the fidelity of cellular signaling within large plasma-membrane-associated macromolecular complexes that are normally deployed to mediate later aspects of neuronal maturation. Targeted loss of these disease-modifier genes can cause neurodegeneration, but it does not promote the occurrence of classical neurodevelopmental abnormalities, because they are not the primary activators of these neuronal differentiation pathways. These cumulative observations suggest that the normal functions of neurodegenerative disease genes may be to orchestrate progressive developmental events associated with the elaboration and maintenance of regional specialized neuronal cell types.

Although Mendelian inheritance has been observed in many neurodegenerative disorders, maternal inheritance can be documented in a subgroup of late-onset mitochondrial diseases that affect both brain and neuromuscular functions. These diseases, known as encephalomyopathies, are associated with mutations in mitochondrial genes that code for components of respiratory chain subunits involved in cellular energy metabolism. In conditions such as Alzheimer's disease and Parkinson's Disease, less than 10 percent of cases display clear genetic inheritance. In these diseases, mutations of several genes that lead to similar clinicopathological profiles have been identified.

By contrast, in Huntington's disease, a clear family history can be identified in essentially all cases. Huntington's disease is the prototype of a subgroup of neurodegenerative diseases that exhibit errors in DNA replication associated with the expansion of repeating triplet sets of nucleic acid residues (trinucleotide repeats ) in the proximal end of the mutant gene, resulting in selective patterns of neurodegeneration. Autosomal dominant disorders within this disease subgroup include Huntington's disease and several forms of hereditary gait instability (e.g., spinocerebellar ataxia, types 1–3 and 6–8). In these disorders, heterozygotes are as severely affected as homozygotes, and the genetic abnormality is thought to endow the mutant protein with novel cytotoxic (toxic to cells) properties. By contrast, in Friedreich's ataxia, an autosomal recessive disorder, disease manifestations are caused by abnormalities in production of the mutant protein, resulting in a loss of the normal cellular function of the involved protein.

There is also a separate category of nongenetic neurodegenerative diseases, as exemplified by the disorder known as Purkinje cell degeneration. In this prominent example of a remote effect of systemic cancer (paraneoplastic disorder), the abnormal production of antibodies to a cytoplasmic protein (cdr2) that normally sequesters an important cell-cycle regulatory protein (Myc) within the cytoplasm of mature cerebellar Purkinje neurons results in unopposed Myc nuclear translocation and inappropriate cell cycle reentry, culminating in neuronal cell death.

Although Alzheimer's disease most often presents clinically in the later decades of life, early-onset inherited forms are now widely recognized. The pathological hallmarks of this disease are the presence of neurofibrillary tangles and senile plaques. Neurofibrillary tangles (NFTs) are composed of aggregates of hyperphosphorylated forms of a microtubular protein called tau. By contrast, senile plaques (SPs) consist of accumulations of several protein species, including β-amyloid (beta-amyloid), in association with a local inflammatory reaction. The role of NFTs and SPs in the occurrence of neurodegeneration is presently unclear. With disease progression, neurons are lost in areas of the hippocampus, entorhinal cortex, and in neocortical-association areas. The genes that code for three transmembrane proteins—β-amyloid precursor protein and presenilin 1 and 2—have been linked to early-onset familial forms of Alzheimer's disease. Mutations in each of these disease genes results in the increased cellular production of a specific form of a cellular protein (β-amyloid 1-42) which is toxic to neurons. β-amyloid precursor protein and the presenilins appear to be important components of developmental pathways involved in neuronal survival and maturation.

Recently, primary mutations in tau have been associated with the presence of neurofibrillary tangles and chromosome 17–linked autosomal dominant forms of frontotemporal dementia. This disorder is characterized by the occurrence of behavioral abnormalities in the absence of memory loss, and progressive dementia associated with the types of motor slowness and rigidity often seen in Parkinson's disease. Pathologically, tau-immunoreactive inclusions are present in neurons and glial cells (non-neuronal) without the concurrent appearance of senile plaques.

The second most common neurodegenerative disease after Alzheimer's disease is Parkinson's disease. This disorder is characterized by the presence of resting tremor, motor slowness, and rigidity. Pathologically, there is loss of cells in the substantia nigra layer of the midbrain, depletion of the neurotransmitter dopamine, and the characteristic presence of Lewy bodies (cytoplasmic inclusions found predominantly within neurons of the substantia nigra). Mutations in several genes have been identified in familial forms of Parkinson's disease. In a related disorder, diffuse Lewy body disease, Lewy bodies are widely expressed within cortical neuronal subpopulations.

Significant clinical and pathological overlap is seen among individual neurodegenerative diseases, particularly between Alzheimer's disease and Parkinson's disease. Parkinson's disease is associated with a high incidence of dementia, and neuropathological studies have documented the occurrence of Lewy bodies, senile plaques, neurofibrillary tangles and the concurrent presence of α-synuclein (alpha-synuclein) and β-amyloid expression. Multiple-system atrophy is a disorder characterized by the presence of autonomic, cerebellar, and extrapyramidal motor signs and symptoms in association with striatonigral and olivopontocerebellar atrophy. In this disorder, α-synuclein immunoreactive neuronal and glial cytoplasmic inclusions occur, establishing links between this neurological condition and both Lewy body disease and Parkinson's disease.

At least eight neurodegenerative diseases are represented within the subclass of trinucleotide repeat disorders, as previously defined. These neurodegenerative diseases are characterized by autosomal dominant or X-linked patterns of inheritance, correlation of the number of trinucleotide repeats with the age of onset and the severity of the disorder, and the presence of anticipation, defined as the tendency for successive generations to exhibit an earlier age of onset. Recent studies suggest that disease pathogenesis involves the preferential ability of mutant proteins to undergo abnormal cleavage by cellular proteases (caspases) to form nuclear and cytoplasmic aggregates, which can impair the actions of important cellular proteins. This mechanism causes alterations in the availability of key developmental and transcriptional regulatory molecules, resulting in subthreshold developmental abnormalities in precursors of vulnerable neuronal subpopulations that later undergo regional cell death. Huntington's disease is an autosomal dominant disorder characterized by behavioral disturbances, dementia, and abnormal limb movements (chorea) in association with a gradient of neuronal cell loss in the neostriatum and the cerebral cortex.

Several subtypes of autosomal dominant spinocerebellar ataxias, characterized by a partially overlapping spectrum of neurological impairments, have been defined by identification of the relevant mutant genes. The protein products, termed ataxins, all have expanded polyglutamine residues. The regional and neuronal selectivity that defines each disease subtype is correlated with the degree of accumulation of abnormal intranuclear fragments of the individual ataxin proteins. By contrast, Friedreich's ataxia, the most common hereditary ataxia, is an autosomal recessive disorder characterized by early age of onset, gait instability, speech impairment, motor disability, sensory loss, skeletal deformities, and cardiac dysfunction. This myriad of clinical signs is associated with neuropathological involvement of the long tracts of the dorsal columns of the spinal cord, the peripheral nerves, and the pyramidal motor system. Mutation of the gene product, frataxin, a mitochondrial protein, results in altered iron metabolism and a severe cellular energy deficit caused by impairments in components of the respiratory chain that predispose to late-onset cell death in selected regions of the nervous system that express the disease gene.

Neurodegenerative diseases also affect different components of the central and peripheral motor pathways, resulting in upper motor-neuron signs (spasticity, weakness and increased deep-tendon reflexes) and lower motor signs (muscle atrophy and weakness). Amyotrophic lateral sclerosis, the most common form of motor-neuron disorder, is defined by relentless progression of weakness and atrophy of muscles innervated by brain-stem and spinal-cord neurons, with conspicuous sparing of those muscles that regulate eye movements and bowel and bladder function. Pathologically, there is widespread death of motor neurons preceded by cellular shrinkage and axonal swelling. Less than 10 percent of cases are familial, and of these approximately 10 to 20 percent have mutations of the superoxide dismutase type 1 gene, which encodes a molecule involved in the regulation of free radical formation. Genetic studies suggest that the gene mutation exhibits selective toxicity for motor neurons.

Spinal and bulbar muscular atrophy (Kennedy's syndrome) is an X-linked disorder of midlife characterized by progressive proximal limb weakness and atrophy associated with extensive loss of androgen-responsive motor neurons. Kennedy's syndrome is one of the trinucleotide repeat disorders.

Hereditary spastic paraparesis may be inherited as autosomal dominant, autosomal recessive, or X-linked conditions that target upper motor neurons, with resulting progressive symmetric leg weakness and spasticity. Both autosomal dominant and recessive forms of the disorder are caused by mutations in genes that code for members of a specific class of proteins, termed AAA proteins. The protein spastin is responsible for dominant forms of the disorder, and paraplegin for recessive forms. Another AAA protein, torsin A, is mutated in a distinctive neurodegenerative disorder resulting in an early-onset movement disorder, torsion dystonia, which is characterized by the presence of abnormal, intermittent motor postures. By contrast, X-linked forms of hereditary spastic paraparesis are caused by mutations in specific genes that can also cause mental retardation or a rare form of dysmyelinating disorder related to multiple sclerosis, termed Pelizaeus-Merzbacher disease.

Finally, there are a series of early-onset autosomal recessive disorders that predominantly affect the lower motor neurons, termed spinal muscular atrophies, that are associated with progressive muscular weakness and atrophy. The vast majority of patients with spinal muscular atrophy have deletions of the survival motor-neuron gene, whereas mutations in two other genes have also been shown to cause spinal muscular atrophy: neuronal apoptosis inhibitory protein and neuromuscular degeneration, which is involved in early stages of DNA damage repair.

Mark F. Mehler

See also Alzheimer's Disease; Brain; Dementia; Dementia with Lewy Bodies; DNA Damage and Repair; Genetics; Neurochemistry; Neuroendocrine System; Parkinsonism; Pathology of Aging, Human.

BIBLIOGRAPHY

Cummings, C. J.; Orr, H. T.; and Zoghbi, H. Y. "Progress in Pathogenesis Studies of Spinocerebellar Ataxia Type 1." Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 354 (1999): 1079–1081.

Goedert, M. "Filamentous Nerve Cell Inclusions in Neurodegenerative Diseases: Tauopathies and α-Synucleinopathies." Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 354 (1999): 1101–1118.

Jones, A. L. "The Localization and Interactions of Huntingtin." Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 354 (1999): 1021–1027.

Martin, J. B. "Molecular Basis of the Neurodegenerative Disorders." The New England Journal of Medicine 340 (1999): 1970–1980.

Mehler, M. F., and Gokhan, S. "Mechanisms Underlying Neural Cell Death in Neurodegenerative Diseases: Alterations of a Developmentally-Mediated Cellular Rheostat." Trends in Neurosciences 23 (2000): 599–605.

Price, D. L.; Tanzi, R. E.; Borchelt, D. R.; and Sisodia, S. S. "Alzheimer's Disease: Genetic Studies and Transgenic Models." Annual Review of Genetics 32 (1998): 461–493.

Ross, C. A.; Wood, J. D.; Schilling, G.; Peters, M. F.; Nucifora, F. C.; Cooper, J. K.; Sharp, A. H.; Margolis, R. L.; and Borchelt, D. R. "Polyglutamine Pathogenesis." Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 354 (1999): 1005–1011.

Sathasivam, K.; Hobbs, C.; Mangiarini, L.; Mahal, A.; Turmaine, M.; Doherty, P.; Davies, S. W.; and Bates, G. P. "Transgenic Models of Huntington's Disease." Philosophical Transactions of the Royal Society of London B 354 (1999): 963–969.

Van Gassen, G.; Annaert, W.; and Van Broeckhoven, C. "Binding Partners of Alzheimer's Disease Proteins: Are They Physiologically Relevant." Neurobiology of Disease 7 (2000): 135–151.

Wong, P. C.; Rothstein, J. D.; and Price, D. L. "The Genetic and Molecular Mechanisms of Motor Neuron Disease." Current Opinions in Neurobiology 8 (1998): 791–799.