Written by Dr. Terri M Driessen Edited by Dr. David Bushart
Mitochondrial dysfunction and loss of mitochondrial DNA is identified in an SCA1 mouse model.
Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder that causes cell death in certain parts of the brain. The brain regions affected play important roles in motor coordination. The loss of coordination and movement – a symptom called ataxia – is the one of the primary effects of this disease. To investigate the causes of SCAs, researchers often use mouse models. In mouse models of SCA1, there are deficits in motor coordination before a significant amount of neurons (i.e., brain cells) are lost. This suggests that changes in neuron function, and not necessarily neuron death, may cause behavioral changes in SCA1. However, the mechanisms that cause dysfunction in SCA1 neurons are still a mystery.
The brain requires a lot of energy to function. Without this energy, our neurons would be unable to survive. The cellular machines that generate this energy are the mitochondria, which are small organelles found in neurons (and nearly every other type of cell, for that matter). If the mitochondria in neurons do not function properly, this could lead to abnormal neuronal functioning. In fact, mitochondrial dysfunction has been found in several neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS, or Lou Gehrig’s disease), Spinal Muscular Atrophy, Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease. Previous studies have also linked mitochondrial dysfunction to SCA1. It has been shown that Purkinje cells, the major cell type affected in SCA1, have altered levels of mitochondria-related RNA and proteins in SCA1 mouse models (Stucki, et al. 2016; Ferro, et al. 2017).
Written by Dr. Marija Cvetanovic Edited by Dr. Maxime W. Rousseaux
New research (published Nov. 2018) reveals promising potential genetic therapy for SCA1.
A research team comprised of scientists from academia and industry have tested a new treatment for Spinocerebellar ataxia type 1 (SCA1), bringing disease-modifying therapy one step closer to the clinic. SCA1 is a dominantly-inherited ataxia that is currently untreatable. Symptoms of the disease include progressive loss of balance, slurring of speech, difficulties with swallowing and coughing, mild cognitive impairments, and depression. With a life expectancy after diagnosis of only 10-15 years, SCA1 is one of the fastest-progressing SCAs: after symptoms first appear, patients typically have just over a decade before these symptoms become so severe that they cause death (often due to respiratory failure). In 1993, collaborative efforts from the laboratories of Drs. Harry T. Orr and Huda Y. Zoghbi discovered that SCA1 is caused by the expansion of a CAG repeat somewhere in a patient’s DNA. CAG repeats cause a polyglutamine expansion in the protein that the mutated gene encodes; in this case, the group later identified that this had occurred in Ataxin-1 (ATXN1), the gene that encodes the ATXN1 protein. The SCA1 mouse models that Drs. Orr and Zoghbi generated (and graciously shared with the scientific community) have allowed for significant advances in the understanding of SCA1 pathogenesis over the years. Now, they provide preclinical evidence of a promising therapy to alter the progressive motor deficits and fatal outcome of SCA1.
Written by Hillary Handler Edited by Dr. David Bushart
How researchers found that SCA1 is caused by an expanded, repetitive DNA sequence – a discovery that has allowed for accurate SCA1 diagnosis and more focused research strategies
Before the true genetic basis of Spinocerebellar Ataxia Type 1 (SCA1) was discovered, researchers and medical doctors noticed that SCA1 causes motor dysfunction, death of specific types of brain cells, and premature death in affected patients. By assessing health outcomes in multiple families affected by SCA1, scientists also recognized that the disease is inherited in an autosomal dominant manner. This means that each person with an SCA1 diagnosis has a 50% chance of passing the disease to each of his or her children. In addition, researchers noticed that affected members of SCA1 families displayed a disease feature called anticipation: a trend of increasing symptom severity and earlier age-of-onset as the disease is passed from generation to generation. Despite these discoveries, the specific genetic mutation responsible for causing SCA1 had not yet been identified or described. Determining the genetic cause of an inherited disease is critical for allowing accurate diagnosis of the condition. Furthermore, understanding the genetics of SCA1 would provide researchers with important clues about disease pathology that could help with designing and developing treatments.
One of the groups that sought to identify the specific genetic cause of SCA1 was led by Dr. Harry Orr. These researchers published their findings in a landmark 1993 paper (Nature Genetics, 1993), which described the process by which they made their discovery. First, a technique called “linkage analysis” was used to determine the general location of the SCA1 gene within the human genome. By tracking how SCA1 is inherited relative to other, well-characterized genetic locations, the team was able to narrow their search to a small portion of chromosome 6’s short arm known as region 6p22-6p23. The researchers also noted that anticipation is often indicative of a particular DNA feature known as a trinucleotide repeat. To determine if a trinucleotide repeat was indeed causing SCA1, these scientists used DNA cloning and screening techniques within the identified region of chromosome 6. These experiments identified a CAG trinucleotide repeat within the SCA1 genomic target region of DNA.
Written by Dr. Laura Bowie Edited by Dr. Hayley McLoughlin
Researchers use genetics to find new pathways that impact the onset of polyglutamine disease symptoms
The cells of the human body are complex little machines, specifically evolved to fulfill certain roles. Brain cells, or neurons, act differently from skin cells, which, in turn, act differently from muscle cells. The blueprints for all of these cells are encoded in deoxyribonucleic acid (DNA). To carry out the instructions in these cellular blueprints, the DNA must be made into ribonucleic acid (RNA), which carries the instructions from the DNA to the machinery that makes proteins. Proteins are the primary molecules responsible for the structure, function, and regulation of the body’s organs and tissues. A gene is a unit of DNA that encodes instructions for a heritable characteristic – usually, instructions for a making a particular protein. If there is something wrong at the level of the DNA (known as a mutation) then this can translate to a problem at the level of the protein. This could alter the function of a protein in a detrimental manner – possibly even rendering it totally non-functional.
DNA is made up of smaller building blocks called nucleotides. There are four different nucleotides: cytosine (C), adenine (A), guanine (G), and thymine (T). Polyglutamine diseases, such as the spinocerebellar ataxias (SCAs) and Huntington’s disease (HD), are caused by a CAG triplet repeat gene expansion, which leads to the expansion of a polyglutamine tract in the protein product of this gene (MacDonald et al., 1993; Zoghbi & Orr, 2000). Beyond a certain tract length, known as the disease “threshold,” the length of this expansion is inversely correlated with age at disease onset. In other words, the longer this expansion is, the earlier those carrying the mutation will develop disease symptoms. However, scientists have determined that onset age is not entirely due to repeat length, since individuals with the same repeat length can have different age of disease symptom onset (Tezenas du Montcel et al., 2014; Wexler et al., 2004). Therefore, other factors must be involved. These factors could be environmental, genetic, or some combination of both.
Written by Dr. Chandrakanth Edamakanti Edited by Dr. Hayley McLoughlin
Recent study decodes the protein signature of toxic Purkinje cells, finding that Purkinje cell mTORC1 signaling is impaired in SCA1.
Spinocerebellar ataxia type 1 (SCA1) is a late onset cerebellar neurodegenerative disorder caused by a mutation (in this case, an abnormal polyglutamine stretch) in the Ataxin-1 gene. People with this condition experience problems with coordination and balance, a set of symptoms known as ataxia. The protein produced by this faulty gene, ATXN1, is particularly toxic to the Purkinje cells, the sole output neurons of the cerebellum. However, the reason behind the selective toxicity of Purkinje cells in SCA1 is unknown.
The main focus of this article is to address this question. It is the first study to find the protein signature of toxic Purkinje cells in SCA1 mice. In the end, the authors identified widespread protein changes that are associated with Purkinje cell toxicity.