Genetic Mechanisms in Degenerative Diseases of the Nervous System
Expanded Trinucleotide Repeats Characterize Several Neurodegenerative Diseases
Spinobulbar Muscular Atrophy Is Due to Abnormal Function of the Androgen Receptor
Parkinson Disease Is a Common Degenerative Disorder of the Elderly
Selective Neuronal Loss Occurs After Damage to Ubiquitously Expressed Genes
Animal Models Are Powerful Tools for Studying Neurodegenerative Diseases
Mouse Models Reproduce Many Features of Neurodegenerative Diseases
Several Pathways Underlie the Pathogenesis of Neurodegenerative Diseases
Protein Misfolding and Degradation Contribute to Parkinson Disease
Protein Misfolding Triggers Pathological Alterations in Gene Expression
Mitochondrial Dysfunction Exacerbates Neurodegenerative Disease
Apoptosis and Caspase Modify the Severity of Neurodegeneration
THE MAJOR DEGENERATIVE DISEASES of the nervous system—Alzheimer, Parkinson, and the triplet-repeat diseases (Huntington and the spinocerebellar ataxias)—afflict nearly 5 million people in the United States alone, and more than 25 million people throughout the world. Although this is a relatively small percentage of the population, these diseases bring a disproportionate amount of suffering and economic loss, not only to their victims but also to the families and friends of the afflicted.
Most of these disorders strike in mid-life or later; aging itself may in fact contribute to susceptibility. With the exception of Alzheimer disease, the first symptoms to appear usually involve loss of control of fine motor movements, although Huntington disease can first manifest itself in cognitive deficits. Nevertheless, the end result is the same. After a lengthy period of progressive deterioration, usually 10 to 20 years, the affected individual dies a terrible, helpless death.
The late-onset neurodegenerative diseases can be grouped conceptually into two categories: sporadic (unknown etiology) and inherited. Alzheimer disease and Parkinson disease are predominantly sporadic; inherited forms afflict a small number of patients. The triplet-repeat diseases, however, are notable for their dominant pattern of inheritance and the dynamic nature of the pathological mutation, an elongation of a CAG repeat tract that is subject to further expansion. Among the triplet-repeat neurodegenerative diseases are Huntington disease, the spinocerebellar ataxias, dentatorubropallidoluysian atrophy, and spinobulbar muscular atrophy. Identification of the molecular basis of some of these disorders has facilitated diagnosis and classification and provides hope for eventual treatment.
Expanded Trinucleotide Repeats Characterize Several Neurodegenerative Diseases
Huntington Disease Involves Degeneration of the Striatum
Huntington disease usually strikes in early or middle adulthood and affects 5 to 10 people per 100,000. The clinical presentation includes loss of motor control, cognitive impairment, and affective disturbance. Motor-control problems most commonly manifest themselves early as chorea, involuntary jerky movement that involves the small joints at first but then gradually creates instability of gait as the trunk and legs are affected. Fast, fluid movements are replaced by rigidity and bradykinesia (difficulty initiating action and unusually slow movements).
Cognitive impairment—such as difficulty in planning and executing complex functions—typically appears along with the involuntary movements but may be detected by formal neuropsychological testing even prior to motor dysfunction. Affective disturbances (psychiatric and behavioral features) include depression, irritability, social withdrawal, and disordered sleep. Hypomania and increased energy occur in 10% of the patients, whereas frank psychosis with delusions occurs in a smaller subset.
In adult patients the disease progresses inexorably to death some 17 to 20 years after onset. Juvenile-onset cases suffer a more rapid course of the disease and within only a few years typically develop bradykinesia, dystonia (spasm of the neck, shoulders, and trunk), rigidity (resistance to the passive motion of a limb), seizures, and severe dementia.
The pathological hallmark of Huntington disease is degeneration of the striatum, with the caudate nucleus being more affected than the putamen. Loss of a class of inhibitory interneurons in the striatum, the medium spiny neurons, reduces inhibition of neurons in the external pallidum (see Chapter 43). The resulting excessive activity of the pallidal neurons inhibits the subthalamic nucleus, which could account for the choreiform movements. As the disease progresses and striatal neurons projecting to the internal pallidum degenerate, rigidity replaces chorea. Abnormalities in corticostriatal projections are thought to contribute to pathogenesis. Juvenile cases suffer a more severe and generalized pathology that often includes cerebellar Purkinje cells.
Huntington disease is an autosomal dominant disorder and one of the first human diseases to have its gene mapped using polymorphic DNA markers. It is caused by expansion of a translated CAG repeat that encodes a glutamine tract in the huntingtin protein. Normal or wildtype alleles have 6 to 34 repeats, whereas disease-associated alleles typically have 36 or more repeats and are quite unstable when transmitted from one generation to the next, especially through paternal germ cells.
The dynamic nature of the mutation, expanding in successive generations, accounts for the greater severity of the disease in juvenile-onset cases, a phenomenon known as anticipation. The length of the repeat correlates inversely with the age of onset, one of the many common features of neurodegenerative diseases caused by CAG-repeat expansions (Figure 44-1). Huntington disease-like 2 (HDL2), a rare neurodegenerative disorder that is clinically similar to Huntington disease, is caused by CTG expansion in junctophilin 3.
Figure 44-1 The length of the CAG repeat and age of onset in spinocerebellar ataxia are inversely correlated. The longer the CAG tract, the earlier the onset for a given disease. Specific repeat lengths, however, have different results depending on the host protein. For example, a 52-repeat of CAG causes juvenile onset of symptoms in spinocerebellar ataxia type 2 (SCA2), adult onset in spinocerebellar ataxia type 1 (SCA1), and no disease in spinocerebellar ataxia type 3 (SCA3).
Huntington disease appears to be a true dominant disease in that patients homozygous for the condition do not differ significantly from their heterozygous siblings. The expanded glutamine tract causes the huntingtin protein to gain toxic function in addition to its normal function. Huntingtin is expressed throughout the brain in the cytoplasm, where it associates with microtubules, with a minor fraction present in cell nuclei. Although its precise functions are unknown, huntingtin is an essential protein in normal embryonic development as shown by mouse knock-out studies; it is also essential for neuronal integrity in the postnatal brain.
Spinobulbar Muscular Atrophy Is Due to Abnormal Function of the Androgen Receptor
Spinobulbar muscular atrophy (Kennedy disease), the only X-linked disorder among the neurodegenerative diseases discussed in this chapter, is caused by expansion of a translated CAG repeat in the androgen receptor protein, a member of the steroid hormone receptor family. Only males manifest symptoms; the mutant androgen receptor is toxic when in the nucleus, and such localization requires the male hormone androgen. Proximal muscle weakness is usually the presenting symptom; eventually the distal and facial muscles weaken as well. Muscle wasting is prominent, secondary to degeneration of motor neurons.
Bulbar dysfunction results from loss of brain stem motor neurons. Many patients also develop gynecomastia, late hypogonadism, and sterility, indicating the loss of androgen receptor function. Individuals lacking androgen receptor function without expansion of CAG repeats do not, however, develop motor neuron degeneration. It thus appears that the glutamine expansion causes a partial loss of function that accounts for the secondary sexual characteristics and a partial gain of function that affects neurons and produces the neurological phenotype.
Hereditary Spinocerebellar Ataxias Include Several Diseases with Similar Symptoms but Distinct Etiologies
The spinocerebellar ataxias and dentatorubropallidoluysian atrophy are dominantly inherited neurodegenerative diseases that, for all their heterogeneity, are characterized predominantly by dysfunction of the cerebellum, spinal tracts, and various brain stem nuclei. The basal ganglia, cerebral cortex, and peripheral nervous system are also affected in some subtypes or in isolated cases (Table 44–1).
Table 44–1 Pattern of Inheritance and Main Clinical Features of Neurodegenerative Diseases Caused by Unstable Trinucleotide Repeats
The two clinical features common to all the spinocerebellar ataxias are ataxia and dysarthria. These typically appear in mid-adulthood and gradually worsen, making walking impossible and speech incomprehensible. The brain stem dysfunction manifests itself through difficulties in swallowing and breathing and eventually causes death.
Features such as chorea or dementia are associated more strongly with one spinocerebellar ataxia than others, but these symptoms are so variable that they cannot be reliably used to refine the diagnosis. Even individuals within the same family can present a quite different clinical picture. Thus, although the spinocerebellar ataxias are singlegene Mendelian disorders, individual genetic makeup and environmental influences clearly affect the clinical-pathological situation.
For example, Machado-Joseph disease and spinocerebellar ataxia type 3 (SCA3) had been regarded clinically as distinct diseases before it was discovered that they are caused by mutations in the same gene. The clinical confusion arose by historical accident. The most prominent features of the Portuguese families first studied by Machado and Joseph were bulging eyes, faciolingual fasciculations, parkinsonism, and dystonia, whereas the first SCA3 patients had features more reminiscent of SCA1 (hypermetric saccades and brisk reflexes in addition to the characteristic ataxia and dysarthria). We now know that these apparent clinical differences are at least partially attributable to differences in length of the CAG repeats. Nonetheless, differences in the activity of other proteins caused by genetic variations are probably also at play.
Although the age of onset within each type of ataxia depends on the number of CAG repeats in the gene (Figure 44-1), the toxicity of the abnormally long glutamine tract in the protein product depends on the protein: Expanded glutamine tracts have different effects in different proteins. For example, very short repeat lengths that are detrimental to Purkinje cells in SCA6 are nonpathogenic in other SCAs. In fact, the CAG expansion in SCA6 is the shortest of all the spinocerebellar ataxias: 21 to 33 repeats in mutants compared to fewer than 18 in normal alleles. In contrast, the gene responsible for SCA7 normally tolerates a few dozen CAG repeats, and in the disease state undergoes some of the largest expansions seen in any spinocerebellar ataxia (hundreds of CAGs). (Table 44-2.) The affected product in dentatorubropallidoluysian atrophy, atrophin-1, is thought to be a corepressor based on functional studies of its probable ortholog in Drosophila. Despite these differences, some patho-genetic mechanisms may be common to the polyglutamine diseases, as discussed later in this chapter.
Table 44–2 Hereditary Ataxias Caused by Expansion of Unstable Trinucleotide Repeats
Besides tolerating different CAG repeat lengths, the gene products of mutated genes in polyglutamine diseases vary widely in function. The affected gene product in SCA1, ataxin-1, seems to be important for learning and memory; it is predominantly a nuclear protein that shuttles to the cytoplasm and can bind RNA in vitro, which suggests that it might play a role in RNA transport and processing. The affected gene product in SCA6, CACNA1A, is the α1A subunit of the voltage-gated Ca2+ channel; interestingly enough, loss-of-function mutations in the gene (not caused by CAG repeats) have been reported in patients with episodic ataxia and familial hemiplegic migraine. In SCA17 the affected gene product is the TATA box-binding protein, an essential transcription factor.
A few spinocerebellar ataxias are caused by unstable trinucleotide repeats other than CAG (Table 44-2). Spinocerebellar ataxia type 8 is caused by an expansion of a CTG repeat in the 3′ untranslated region of a transcribed RNA with no open reading frames. The mutation responsible for SCA12 is a CAG repeat, but it occurs in a noncoding region upstream of a brain-specific regulatory subunit of the protein phosphatase 2A. Spinocerebellar ataxia type 10 is unique in that it is caused by massive expansion of a pentanucleotide (ATTCT) repeat in the intron of a novel gene. The pathogenic mechanisms accounting for the dominant phenotypes in spinocerebellar ataxia types 8, 10, and 12 are not yet known.
Parkinson Disease Is a Common Degenerative Disorder of the Elderly
Parkinson disease, one of the more common neurodegenerative disorders, affects 1% to 2% of the population older than 65 years of age. Patients with Parkinson disease suffer from a resting tremor, bradykinesia, rigidity, and impairment in their ability to initiate and sustain movements. Affected individuals walk with a distinctive shuffling gait, and their balance is often precarious. Spontaneous facial movements are greatly diminished, such that the face has a mask-like, expressionless appearance. The pathological hallmark of Parkinson disease is progressive loss of dopaminergic neurons, mainly in the substantia nigra (see Chapter 43).
Although the majority of parkinsonian cases are sporadic, studies of rare familial cases have provided insight into the genetic factors that predispose individuals to this disorder. Here we focus on how the genetic bases of some forms of Parkinson disease provides insights into sporadic Parkinson disease and link the pathogenic mechanism of parkinsonism to that seen in the polyglutamine disorders.
Both autosomal dominant and recessive inheritance patterns have been documented in familial parkinsonism. To date, several genetic loci have been mapped (designated PARK1–PARK8, PARK10, and PARK11), and the genes for all but three of these loci (PARK3, PARK10, and PARK11) have been identified (Table 44–3).
Table 44–3 Genetics and Main Clinical Features of Inherited Parkinson Disease
Parkinson disease type 1 (PARK1) is the locus for the dominantly inherited Parkinson disease caused by mutations in the gene α-synuclein. Two mutations in α-synuclein have been identified: A53T has been described in several Greek families, whereas A30P has been identified in one German family. Mutations in α-synuclein have not been identified in sporadic Parkinson disease. However, because the α-synuclein protein is a primary component of the Lewy bodies in the substantia nigra of patients with sporadic disease as well as those with PARK1, α-synuclein mutations could play an important role in the pathogenesis of the sporadic disease.
The function of the α-synuclein protein is not yet known, but its abundance in presynaptic terminals suggests a role in presynaptic function and perhaps synaptic plasticity. Patients with α-synuclein mutations differ from those with sporadic Parkinson disease in that the age of onset is earlier (a mean of 45 years), and they exhibit fewer tremors and more rigidity, cognitive decline, myoclonus, central hypoventilation, orthostatic hypotension, and urinary incontinence.
Parkinson disease type 2 (PARK2) is an autosomal recessive disease characterized by early onset (as young as three years of age), dystonia, brisk deep-tendon reflexes, and cerebellar signs in addition to the classic Parkinson disease phenotype. More than 60 different mutations have been identified in the gene PARK2, and most are clearly inactivating, demonstrating that this form of the disease is caused by loss of function of the gene product, parkin. Whereas α-synuclein mutations have not been detected in the sporadic disease, mutations in the parkin gene have been found in isolated cases of early-onset Parkinson disease and in one patient with onset at 65 years of age. Loss of dopaminergic neurons in the substantia nigra is typical of this form of the disease, but Lewy bodies are not as common as in sporadic or PARK1 cases.
The parkin gene encodes an E3 ubiquitin ligase of the RING-finger family that transfers activated ubiquitin to lysine residues in proteins destined for degradation by proteasomes. The ligase is quite specific and transfers ubiquitin to only a few substrates. Some substrates for parkin have been identified, including a putative transmembrane G protein-coupled receptor named parkin-associated endothelin receptorlike receptor (Pael-R), the synaptic vesicle protein CDCrel-1, the O-glycosylated form of α-synuclein, the α-synuclein interactor synphilin-1, and parkin itself.
A missense mutation, I93M, in the gene encoding ubiquitin C-terminal hydrolase-L1 (UCH-L1) has been identified in a family with an apparently autosomal dominant Parkinson disease, PARK5. UCH-L1 is an abundant protein in the brain and is thought to cleave polyubiquitin chains as the ubiquitinated proteins are being degraded by the proteasome. This activity is decreased in individuals with the 193M mutant. A homologous protein is necessary for the formation of memory in the marine mollusk Aplysia.
Parkinson disease type 6 (PARK6) is caused by mutations in a gene that encodes a PTEN-induced putative kinase 1 (PINK1), a mitochondrial protein kinase, whereas Parkinson disease type 7 (PARK7) is caused by mutations in a gene that encodes DJ-1, a protein that may function as a sensor of oxidative stress. Mutations in the gene encoding the leucine-rich repeat kinase 2 (LRRK2) cause Parkinson disease type 8 (PARK8) as well as a small percentage of sporadic Parkinson disease cases.
Selective Neuronal Loss Occurs After Damage to Ubiquitously Expressed Genes
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