Introduction 

Classed as a spinocerebellar ataxia, Machado–Joseph Disease (MJD) is an inherited neurodegenerative disorder, marked by progressive impairments in movement, coordination, and mood. Affected individuals gradually lose the ability to walk, write, and perform daily tasks, with many requiring a wheelchair within 10-20 years of diagnosis. Although some patients exhibit average life expectancies, those with more aggressive MJD subtypes can have lifespans as short as 30 years.¹ 

There is no available cure, therefore research into the mechanisms underlying MJD is critically important. This article collates existing knowledge, explaining the genetic basis of Machado-Joseph disease hallmarks such as protein misfolding and aggregation, and exploring the ways in which these processes appear to contribute to observed neuronal death. 

What is machado-joseph disease? 

Otherwise termed spinocerebellar ataxia type 3, Machado-Joseph disease (MJD) is the most common of over 30 types of spinocerebellar ataxias: a group of rare genetic disorders in which the gradual death of neurons (neurodegeneration) gives rise to progressive deficits in muscle control and coordination (ataxia).² Observed motor impairments in MJD patients are linked specifically to degeneration in brain structures known as the cerebellum and brainstem, as well as the upper spinal cord.³ 

Despite considerable variation among patients, core symptoms include:²

• Impairments in balance and coordination of limbs
• Bradykinesia - slowness of movement
• Gait abnormalities
• Dysphagia - trouble swallowing
• Dysarthria - trouble speaking
• Cognitive impairments e.g., memory, focus, mood 
• Visual impairments

There are three clinical subtypes of Machado-Joseph disease, stratified by age of onset and symptom progression:²

• Type I
  • Early onset: ages 10-30
  • Severe symptoms, with rapid progression
    • Severe dystonia: involuntary muscle spasms
    • Rigidity 
• Type II
  • Onset: ages 20-50
  • Symptoms progress gradually with time
    • Spasticity: uncontrolled muscle spasms
• Type III
  • Onset: ages 40-70
  • Slow symptom progression
    • Peripheral neuropathy: pain, tingling, or numbness of extremities

Diagnosis typically combines physical and neurological examination with the assessment of the family medical history, neuroimaging to identify affected brain regions, and confirmatory genetic testing. Given that observed symptoms overlap with several other neurological disorders, including Parkinson’s disease, multiple sclerosis, and other types of spinocerebellar ataxias, accurate diagnosis is critical to inform treatment strategy.² Although there remains no cure for MJD, current approaches are multidisciplinary, combining physical therapy, speech therapy, and pharmacological interventions to manage the specific symptoms of the affected individual.¹ 

Ataxin-3 and the ubiquitin proteasome system 

The specific disease-causing mutation carried by Machado-Joseph patients is located in the ATXN3 gene, found on chromosome 4 and encoding a protein called ataxin-3. To understand the underlying disease mechanisms of MJD, we must first examine the function of the affected protein in healthy individuals. 

Ataxin-3 is well-understood to be a key component of the ubiquitin-proteasome system (UPS): the pathway by which our cells remove damaged, misassembled, or excess proteins.^3,4 The first step of this waste-disposal process is ubiquitination, where unwanted proteins are tagged with a small molecule called ubiquitin. Depending on the position and number of attached ubiquitin chains, this chemical label guides the protein towards pathways for degradation, repair, or transport.⁵

Known as a deubiquitinating (DUB) enzyme, ataxin-3 removes ubiquitin chains from marked proteins that would otherwise be degraded by the proteasome: a multimolecular cellular machine that breaks down ubiquitinated proteins. By removing this molecular tag, ataxin-3 rescues target proteins from destruction, allowing them to be recycled or, in some cases, to accumulate within the cell. When this quality-control process is disrupted, this ensures build-up of damaged and misfolded proteins can become toxic, triggering cell death. For example dysfunction of the UPS therefore implicating not only in Machado-Joseph Disease, but also in several other neurodegenerative disorders, including Alzheimer's, Parkinson’s, and Huntington’s disease.³ 

The genetic basis of MJD

The aforementioned mutation in the ATXN3 genes of Machado-Joseph disease patients is classed as a trinucleotide repeat expansion. Providing the instructions for building proteins, there are four main components of DNA, known as the nucleotide bases: adenine (A), cytosine (C), guanine (G), and thymine (T). These bases are read in sets of three (triplets), with each triplet specifying a particular amino acid: the building blocks of proteins. 

As a trinucleotide repeat disorder, MJD is characterised by excess repetitions of the sequence CAG, which codes for an amino acid called glutamine. While healthy individuals exhibit 12-43 consecutive CAG triplets in the ATXN3 gene, MJD patients have 56-86. This change in the genetic code builds a version of the ataxin-3 protein that contains an unusually long chain of glutamine, known as a polyglutamine expansion.¹ 

The exact number of CAG repeats is proportional to the severity of symptoms and the age of disease onset, with larger expansions generally resulting in more aggressive Machado-Joseph disease subtypes. Following an autosomal dominant pattern of inheritance, only one copy of the faulty ATXN3 gene is needed to cause disease, meaning that each child of an affected parent has a 50% chance of developing MJD. Interestingly, the number of repeats typically increases between generations, with the age of onset decreasing accordingly. This is a phenomenon called anticipation, and is particularly pronounced when the disease is inherited from one’s father.³

Protein misfolding in machado-joseph disease

Once assembled, the long chains of amino acids comprising a protein must fold into stable three-dimensional structures (conformations), specified by the sequence of the constituent amino acids themselves. For example, in healthy individuals, the ataxin-3 protein folds into spiral-like structures called alpha-helices. In Machado-Joseph disease patients, however, excess glutamine repeats drive ataxin-3 to misfold, instead forming pleated structures known as beta-sheets. In this mutant form, ataxin-3 molecules exhibit a tendency to clump together, forming protein aggregates within cells. 

It is a well-established tenet of biology that structure and function are inextricable, and the misfolding of ataxin-3 is no exception. While the impact of mutations on the deubiquitinating activity of ataxin-3 may vary by brain region, preclinical studies consistently highlight resulting impairments in protein quality control. In the absence of deubiquitination by functional ataxin-3, a larger proportion of tagged proteins are transported to the proteasome for degradation. In particular, this seems to upregulate the destruction of protein components of the proteasome itself, essentially breaking down the machine that degrades proteins. Simultaneously, ataxin-3 mutations appear to decrease the degradation of misfolded proteins. The overall effect is the build-up of protein aggregates within neurons, composed not only of ataxin-3, but also ubiquitin and other damaged proteins. In MJD, these inclusions typically occur in the neurons of the brainstem, cerebellum, and spinal cord, contributing to observed neuronal death in these areas.³ 

How does protein misfolding lead to neurodegeneration in MJD?

The precise mechanisms linking protein misfolding and neurodegeneration in Machado-Joseph disease are not fully characterised. What is apparent, however, is that the accumulation of misfolded proteins inside neurons is a common feature across almost all neurodegenerative diseases, including Alzheimer's, Parkinson’s, and Huntington’s disease.⁶ 

Some proposed mechanisms by which aggregates trigger neuronal death include:⁷ 

• Disrupted protein function: aggregates bind and sequester proteins needed for stress responses, DNA repair, protein synthesis, and protein degradation
• Disrupted protein clearance: aggregates overwhelm the ubiquitin-proteasome system, impairing the degradation of toxic protein fragments
• Mitochondrial stress: breakdown of the ubiquitin-protease system impairs degradation of damaged mitochondria: the cell component required for respiration
  • Defective mitochondria accumulate within cells, leaking harmful, inflammatory molecules, called reactive oxygen species
• Inflammation: misfolded protein aggregates trigger the immune system, activating cells called microglia and astrocytes, which attack affected neurons
• Impaired transport within cells: aggregates trap molecules being transported, including neurotransmitters required to transmit signals between neurons

Despite these theories, debates persist as to whether these aggregates are a cause of neuronal death, or merely a result. Some suggest that they are actually neuroprotective rather than neurotoxic, sequestering damaged protein fragments that would otherwise wreak havoc inside the cell. A popular viewpoint suggests that aggregates are initially neuroprotective, but later become damaging, trapping essential proteins and cellular machinery. 

Current and emerging therapeutic approaches

With current treatment plans for Machado-Joseph disease limited to symptom management, efforts are ongoing to develop therapeutic approaches that may slow or prevent disease progression itself.

• Biomarker identification: blood samples from patients and unaffected relatives are under analysis to find measurable molecular indicators of MJD (biomarkers) that may be used to monitor disease progression⁸
• Gene silencing therapies: experimental methods such as antisense oligonucleotides and RNA interference to reduce production of mutant ataxin-3
  • Early studies in mice report reduced protein aggregation and improved motor function
• Deep brain stimulation: non-invasive technique aiming to improve motor function and mood by adjusting brain activity⁹
  • Clinical studies report rapid improvements in ataxia symptoms
• Gene editing: using tools such as CRISPR to correct or silence the mutant ATXN3 gene
• Molecular chaperones: small molecules designed to help cells clear or refold misfolded proteins
• Immunotherapy: modulates the immune response to reduce harmful inflammation and increase clearance of mutant ataxin-3¹⁰
• Stem cell therapy: using immature, adaptable cells to replace damaged/dead neurons¹¹

Summary 

Machado-Joseph disease arises from a mutation in the ATXN3 gene, producing an abnormally sticky, misfolded version of a protein called ataxin-3. Forming aggregates within cells, which overwhelm cellular waste disposal systems, mutant ataxin-3 contributes to the gradual death of neurons in motor regions of the brain. Clinically, this gives rise to progressive deficits in coordination and movement. Ongoing research aims not only to clarify the Machado-Joseph disease mechanisms, but also to gain insight into shared pathways driving other similar neurodegenerative diseases.