Researchers at Northwestern University (NU) have published research showing that changes in the brain causing spinocerebellar ataxia type 1 (SCA1) occur at a younger age than previously thought, reports NeuroscienceNews.
The study, published in the Journal of Clinical Investigation, has important implications for the understanding of SCA1 disease progression and treatment. Furthermore, scientists are now speculating that other degenerative diseases involving the brain, including Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, may develop through similar mechanisms.
SCA1 is a progressive disease that interrupts normal muscle function. It usually first appears in early adulthood, and affects approximately 1 to 2 people per 100,000 worldwide. It is typically characterised by symptoms including difficulties with balance and coordination, muscle stiffness, and problems speaking and swallowing. Patients may also have cognitive impairments relating to learning, memory, and processing.
SCA1 is caused by a mutation of the ATXN1 regulating gene, which produces the protein ataxin-1. When the ATXN1 gene mutates, the ataxin-1 proteins that it produces are the wrong shape. These then build up within the brain and central nervous system causing cell damage, and this occurs at a particularly high frequency in a brain region called the cerebellum. The resulting cell damage and death cases the visible symptoms of the disease.
Most research into this process has focused on changes to neurons, but because gene expression is usually affected early on, researchers at NU looked at how the cerebellar stem cell population was affected to understand the early development of the disease. The research team studied mouse models genetically engineered to have SCA1, and found that important changes to the neural circuitry of the cerebellum occurred in the first postnatal weeks of life, far before other signs of the disease occur.
The mutated version of ATXN1 present in SCA1 patients caused postnatal cerebellar stem cells to proliferate far more than usual, and also led to their differentiation into a type of inhibitory neuron called basket cells. Since the ATNX1 gene caused more basket cells than usual to be produced, the inhibitory effect that they have on Purkinje neurons (a common output neuron in the cerebellum) was increased. This led to atypical development of the cerebellar network. These changes may account for the later sensitivity of the cerebellum to a build-up of the ataxin-1 proteins later in life that cause the symptoms of SCA1.
A secondary effect of excessive numbers of stem cells turning into basket cells is that there were fewer stems cells left to become astrocytes (brain cells), which may also cause some of the symptoms associated with SCA1. Dr Puneet Opal, a senior author of the study, suggests that these changes to the network could cause stress, contributing to the deterioration of the network in later life.