Michael Lodato Receives National Ataxia Foundation Grant

Michael Lodato, PhD, has been awarded a one-year Research Seed Money Grant from the National Ataxia Foundation to support his project, Single-cell somatic mutation analysis in Ataxia Telangiectasia.

Ataxia Telangiectasia (AT) is a rare, inherited multisystem disorder characterized by progressive neurodegeneration of cerebellar Purkinje cells, leading to loss of motor coordination (ataxia). The disease is caused by mutations in the ATM gene, which encodes a protein that plays a pivotal role in orchestrating the repair of DNA damage. Exactly how loss of ATM function leads to Purkinje cell degeneration is not well understood.

The Lodato Lab is uniquely positioned to address this question. The lab studies how somatic mutations arise in the human brain and how they contribute to both normal aging and neurodegenerative diseases, including Alzheimer’s and AT. Detecting these somatic mutations is technically challenging, as they arise at a low frequency and, because neurons are postmitotic, are confined to individual cells.

To overcome this challenge, the lab has developed a single-cell whole-genome sequencing approach capable of detecting somatic single nucleotide variants in individual neurons. Using this strategy, they have previously shown that AT prefrontal cortex neurons, which are minimally affected in the disease, exhibit increased levels of specific classes of somatic mutations compared with control cortical neurons. These findings raise the question of whether the more vulnerable Purkinje cells also harbor elevated somatic mutation levels that may contribute to their dysfunction and degeneration.

In this project, Dr. Lodato hypothesizes that loss of ATM function in Purkinje cells leads to the accumulation of somatic mutations, contributing to altered gene expression and neuronal dysfunction and degeneration. To test this hypothesis, a graduate student in his lab, Bradley Class, will apply single-cell whole-genome (DNA) and whole-transcriptome (RNA) sequencing analysis to determine whether Purkinje cells exhibit increased somatic mutation burdens in AT and, if so, to define the associated mutational signatures, which may provide insight into the mechanisms generating these mutations. He will further assess how these mutations impact gene expression and validate functional consequences using human induced pluripotent stem cell (iPSC)-derived Purkinje cell-like neurons.

By elucidating the mutational mechanisms underlying neurodegeneration in AT, this study ultimately aims to advance the development of novel therapeutic strategies. In addition, because Purkinje cell degeneration is a hallmark of multiple ataxias, the findings may have broader implications for understanding shared disease mechanisms across ataxia disorders.