Last Updated: May 15, 2024
Introduction to the Spinocerebellar Ataxias
The spinocerebellar ataxias (SCA) represent a group of autosomal dominant neurological disorders characterized by variable degrees of degeneration in the cerebellum, spinocerebellar tracts, and brain stem neurons. The shared clinical features of the SCA are ataxia, dysarthria (speech disorder characterized by poor articulation), and ultimately bulbar dysfunction (defective muscle control of throat, tongue, jaw, and face).
Spinocerebellar ataxias are characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. The symptoms of the condition vary with the specific type and with the individual patient. Generally, a person with ataxia retains full mental capacity but may progressively lose physical control.
At least 20 different SCA have been clinically characterized, and of these, eight have been molecularly characterized and shown to be caused by expansion of a trinucleotide repeat in the affected gene. SCA 1, 2, 3, 6, 7, 12, and 17 belong to the polyglutamine (polyQ) family of trinucleotide repeat disorders while SCA 8 belongs to the family of non-polyglutamine family of trinucleotide repeat disorders.
The polyglutamine family of trinucleotide repeat disorders is so-called because the disorder results from the expansion of a CAG trinucleotide in the coding region of the gene and the CAG codon codes for glutamine. As indicated, over 20 dominantly inherited SCA have been identified but this discussion will cover only ten of these disorders.
Descriptions of the Spinocerebellar Ataxias
SCA1
This was the first inherited spinocerebellar ataxia described. SCA1 belongs to the polyglutamine family of trinucleotide repeat disorders. Symptoms of SCA1 usually manifest by the 4th decade and last an average of 15 years before resulting in death. Although numerous kindreds of SCA1 have been described there is extensive intra- and inter-familial variability in observed symptoms. However, all affected individuals suffer from ataxia, dysarthria, and eventual bulbar dysfunction. During the early onset of symptoms patients describe a loss of limb coordination, unstable gait, slurred speech and loss of control in handwriting. Due to bulbar muscle involvement, a cough, representing a throat-clearing action, often precedes the onset of disease. Hypermetric saccades (fast movement of the eyes) and nystagmus (involuntary eye movements) are also seen in the early stages of SCA1.
As the disease progresses the ataxia worsens and other cerebellar signs, such as dystonia, appear. In the final stages of the disease there is brain stem involvement resulting in facial weakness, increased bulbar dysfunction, severe dysarthria and frequent choking spells. Patients often succumb to aspiration and pneumonia as a result the loss of ability to cough effectively.
SCA1 is caused by expansion of a CAG trinucleotide repeat in the ataxin-1 gene (symbol ATXN1) located on chromosome 6p22.3 and is composed of 11 exons that generate three alternatively spliced mRNAs. As a result of the use of multiple alternative translation initiation sites, several distinct protein isoforms are encoded. Due to the variable number of CAG repeats, the ataxin-1 protein, in normal individuals, is composed of approximately 800 to 825 amino acid. In normal individuals the length of the CAG repeat in the ATXN1 gene is 6–44 whereas in affected individuals it ranges from 39–82.
Ataxin-1 is widely expressed in the CNS and has been localized to the nucleus of neurons and the cytoplasm of nonneuronal cells. The most severe pathological alterations seen in SCA1 are restricted to loss of Purkinje cells in the cerebellar cortex. In order for mutant ataxin-1 protein to exert its effect it must enter the nucleus of Purkinje cells.
The exact function of the ataxin-1 protein is not known but it is inferred from recent data that the protein serves as a component of transcriptional repressor complexes. Ataxin-1 has been shown to bind RNA and to interact with several transcription factors. Mutant ataxin-1 protein can repress transcription in the presence of the activated form of a binding partner of the C-terminal domain of RNA polymerase II. This protein is known as polyQ binding protein (PQBP-1). Ataxin-1 also interacts with several transcriptional corepressors including “silencing mediator of retinoid and thyroid hormone receptors” (SMRT), histone deacetylase 3 (HDAC3), and capicua transcriptional repressor (CIC). One important domain in the ataxin-1 protein that may be crucial for its activity is called the AXH (for “ataxin-1 and HMG-box protein 1”) domain.
Another protein involved in ataxin-1 function, called “brother of ataxin-1” (Boat), also contains an AXH domain. Boat is also known as “ataxin-1-like” (ATXN1L). The importance of Boat was demonstrated by the fact that a complex of wild-type ataxin-1 and Boat can reduce the neurotoxic effects of mutant ataxin-1 in mice.
SCA2
Symptoms of SCA2 usually manifest by the 3rd or 4th decade and last an average of 10 years before resulting in death. SCA2 belongs to the polyglutamine family of trinucleotide repeat disorders. Clinical features of SCA2 include ataxia and dysarthria. Most patients exhibit extremely slow saccades with nystagmus preceding the onset of the slow eye movements. Dysphagia (disordered eating) and bulbar failure occur in the late stages of the disease.
SCA2 is caused by expansion of a CAG trinucleotide repeat in the ataxin-2 gene (symbol ATXN2) located on chromosome 12q24.12 spanning 130 kb and composed of 27 exons that generate four alternatively spliced mRNAs, each of which encode a distinct protein isoform. The CAG repeat in the ATXN2 gene resides in exon 1. In normal individuals the length of the CAG repeat is 15–24 whereas in affected individuals it ranges from 32–200.
Although the exact function of the ataxin-2 protein is not known its function has been linked to many biological functions including receptor-mediated signaling, secretion, formation of actin filaments, apoptosis, and cell specification. Evidence that ataxin-2 functions in RNA metabolism is demonstrated by the presence of a domain in the protein called an LSm domain. LSm stands for “like Sm” and the Sm proteins are RNA-binding proteins first identified as antigens in patients suffering from systemic lupus erythematosus (SLE). Another RNA-binding domain found in the ataxin-2 protein is called a PAM2 motif which is involved in binding to the poly(A)-binding protein, PABP. Ataxin-2, like ataxin-1, has also been shown to have a binding partner which is called ataxin-2 binding protein (A2BP). A2BP also contains a putative RNA-binding motif.
Ataxin-2 protein has been localized to the cytoplasm of cells and is found with highest levels in the ependyma and choroid plexus. High levels of protein were also found in cerebellar Purkinje cells and the levels of protein in these cells increases with age in normal individuals with more seen in persons with SCA2.
SCA3 (also called Machado-Joseph disease, MJD)
The alternate name for SCA3 is derived from the two families in which the disease was first described. SCA3 belongs to the polyglutamine family of trinucleotide repeat disorders. Clinical features of SCA3 include progressive ataxia, bulging eyes, muscle weakness, spasticity, Parkinsonism, dystonia and facial fasciculations.
SCA3 is caused by expansion of a CAG trinucleotide repeat in the ataxin-3 gene (symbol ATXN3, also identified as the MJD1 gene) located on chromosome 14q32.12 spanning 48 kb and composed of 13 exons that generate 12 alternatively spliced mRNAs. In normal individuals the length of the CAG repeat is 13–36 whereas in affected individuals it ranges from 61–84.
Ataxin-3 protein has been localized to the cytoplasm of cells particularly those of the striatum and in the nucleus associated with the inner nuclear matrix. Although the exact function of the ataxin-3 protein is still being resolved it appears to be a member of a novel family of cysteine proteases active in ubiquitin-proteasome mediated protein degradation pathway. The ataxin-3 protein contains a Josephine domain (JD) that has ubiquitin protease activity and two ubiquitin interacting motifs (UIMs) that are capable of binding ubiquitin. These data indicate that the likely principal activity of ataxin-3 is as a deubiquitylating enzyme (DUB).
Work demonstrating this proposed role of ataxin-3 in ubiquitin-mediated processes was carried out in fruit flies. Wild-type ataxin-3 was capable of protecting Drosophila neurons from the toxic effects of other polyglutamine-expanded proteins and this activity was dependent upon active proteasomes as well as the ubiquitin protease domain and the UIM domains of ataxin-3. Ataxin-3 is also postulated to have ubiquitin-proteasome system regulating activity in the nucleus leading to regulation of transcription. The C-terminal region of ataxin-3, which contains the polyglutamine stretch, is capable of interaction with CBP (CREB-binding protein: CREB refers to cAMP responsive element-binding protein), p300, and PCAF (p300/CBP associated factor) leading to repression of transcription mediated by these transcriptional coactivators. CBP and p300 are closely related proteins that form one of the families of histone acetyltransferases.
SCA4
SCA4 is a disorder characterized by progressive cerebellar ataxia, dysarthria, extensor plantar reflexes, areflexia and loss of vibration and position sense. The disease usually manifests in the 4th or 5th decade of life. SCA4 was originally not thought to be a member of the trinucleotide repeat class of spinocerebellar ataxias but work published in 2024 demonstrated that a polyglycine (GGC) expansion in the ZFHX3 (zinc-finger homeobox 3) gene is the cause of SCA4. The ZFHN3 encoded protein is also known as AT-binding transcription factor 1 (ATBF1). The expansion of the polyglycine in the ZFHX3 encoded protein disrupts its ability to participate in the normal processes of autophagy in neurons.
SCA5
SCA5 represents the mildest form of the dominantly inherited ataxias. Patients suffer from mild defects in gait and coordination of the limbs. Patients with SCA5 do not experience bulbar involvement and thus have normal life spans. SCA5 is not a member of the trinucleotide repeat class of spinocerebellar ataxias. Mutations in the spectrin, beta, nonerythrocytic, 2 (SPTBN2) gene have been shown to be the cause of this form of spinocerebellar ataxia.
The SPTBN2 gene is located on chromosome 11q13.2 and is composed of 45 exons that generate two alternatively spliced mRNAs encoding proteins of 2390 amino acid (isoform 1) and 2397 amino acids (isoform 2).
SCA6
Symptoms of SCA6 include gait and limb ataxia as well as dysarthria and horizontal gaze-evoked nystagmus. In patients who have been exhibiting symptoms for more than 5 years dysphagia will be a frequent complication. SCA6 is distinguished from other ataxias in that patients do not normally exhibit extrapyramidal signs, visual deficits or spasticity. SCA6 belongs to the polyglutamine family of trinucleotide repeat disorders.
SCA6 is caused by expansion of a CAG trinucleotide repeat in the α1A-transmembrane subunit of the P/Q-type voltage-gated calcium channel gene (CACNA1A). In normal individuals the length of the CAG repeat is 4–19 whereas in affected individuals it ranges from 10–33. Like other voltage-dependent calcium channel proteins, the CACNA1A protein mediates entry of calcium ions into excitable cells. In addition, the C-terminal α1A fragment of the CACNA1A protein has been shown to localize to the nucleus suggesting that the protein may also be involved in regulating nuclear processes.
The CACNA1A gene is located on chromosome 19p13.13 and is composed of 49 exons that generate five alternatively spliced mRNAs, each of which encode a distinct protein isoform. The highest levels of expression of the CACNA1A gene are within the brain.
SCA7
The earliest signs of SCA7 are usually visual deficits or cerebellar ataxia. Patients will experience progressive loss of central vision but maintain peripheral and night vision. Additional symptoms of SCA7 are slow saccades, spasticity, increased reflexes and hearing deficits. Extrapyramidal symptoms in SCA7 include dystonia, limb rigidity and tremors. SCA7 belongs to the polyglutamine family of trinucleotide repeat disorders.
SCA7 is caused by expansion of a CAG trinucleotide repeat in the ataxin-7 gene (ATXN7). The ATXN7 gene is located on chromosome 3p14.1 and is composed of 22 exons that generate five alternatively spliced mRNAs that collectively encode three distinct protein isoforms. The CAG repeat is located in exon 3 beginning at codon 30 of the ataxin-7 protein. In normal individuals the length of the CAG repeat in the ATXN7 gene is 4–35 whereas in affected individuals it ranges from 37–306.
The ataxin-7 protein has been localized to the nucleus, nuclear matrix and nucleolus of cells and is implicated in histone acetyltransferase activity. Ataxin-7 is a subunit of the GCN5 histone acetyltransferase complexes, TFTC and STAGA. The GCN genes were first identified in yeast and shown to be involved in “general control of nitrogen” metabolism. TFTC stands for “TATA-binding protein-free TBP (TATA-box binding protein)-associated factor-containing complex” and STAGA stands for SPT3(suppressor of Ty 3)/TAF(TBP-associated factor) GCN5 complex.
SCA8
The symptoms of SCA8 normally appear in the 4th decade. Symptoms include ataxia, dysarthria, nystagmus and limb spasticity. The disease usually progresses slowly and affected individuals live a normal life span. SCA8 belongs to the non-polyglutamine family of trinucleotide repeat disorders.
SCA8 is caused by expansion of a CTG trinucleotide repeat in the ataxin-8 opposite strand lncRNA gene (symbol ATXN8OS, also called the SCA8 gene) located on chromosome 13q21.33 and is composed of 5 exons. In normal individuals the length of the CTG repeat is 16–34 whereas in affected individuals it is >74.
The SCA8 RNA is a long non-protein coding RNA (lncRNA) produced by antisense transcription from the KLHL1 gene (human homolog of the Drosophila KELCH gene). It is presumed that the expansion of the CTG repeat interferes with the normal function of this antisense transcript.
SCA12
The typical symptoms of SCA12 include those of classic spinocerebellar ataxia. Most individuals presented in the 4th decade with upper extremity tremor, progressing over several decades to include head tremor, gait ataxia, hyperreflexia, paucity of movement, abnormal eye movements, and, in the oldest subjects, dementia. SCA12 belongs to the polyglutamine family of trinucleotide repeat disorders.
SCA12 is caused by expansion of a CAG trinucleotide repeat in the protein phosphatase 2 (formerly 2A), regulatory subunit B, beta isoform (symbol PPP2R2B) located on chromosome 5q32 and is composed of 15 exons that generate eight alternatively spliced mRNAs, each of which encode a distinct protein isoform. In normal individuals the length of the CAG repeat is 7–45 whereas in affected individuals it is 55–78. The PPP2R2B protein is a subunit of the protein phosphatase 2A (PP2A) serine/threonine phosphatase complex.
SCA17
SCA17 is unique among the SCAs in that it is inherited in a pattern similar to that of Huntington disease. SCA17 is also referred to as Huntington disease-like 4 (HDL4). Symptoms of SCA17 include ataxia, dementia, and bradykinesia (slowed ability to start or stop movements). SCA17 belongs to the polyglutamine family of trinucleotide repeat disorders.
SCA17 is caused by expansion of a CAG trinucleotide repeat in the TATA-box binding protein gene (symbol TBP) located on chromosome 6q27 and is composed of 8 exons that generate two alternatively spliced mRNAs each of which encode distinct protein isoforms. In normal individuals the length of the CAG repeat is in TBP is 25–42 whereas in affected individuals it ranges from 47–63.
TBP is the DNA-binding subunit of the multi-subunit transcriptional complex, RNA polymerase II transcription factor D (TFIID). TFIID is the first complex to bind to DNA in the process of transcription and this binding is essential for initiation of transcription. The identification of the role of TBP in SCA17 presents a perplexing question: how does a mutation in a protein that is not only expressed in a wide range of different cell types but is essential for transcription result in neurodegenerative disease in a restricted population of neurons?