Authors:

Akila Abeyaratna

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About Paper:

The DNMT1 gene encodes the enzyme DNA methyltransferase 1, which is crucial for replicating and maintaining DNA methylation patterns during cell division. A specific mutation in this protein, Y511C, causes Hereditary Sensory Autonomic Neuropathy Type 1E (HSAN1E). HSAN1E is an aggressive neurodegenerative disorder that results in sensory neuropathy, global brain atrophy, and hearing loss typically beginning between ages 20-30, and becomes fatal at age 50. The research on this condition is limited, primarily relying on mouse models. To bridge this gap, our lab has pioneered the use of 3D brain organoids, which are clusters of neurons that can mimic the complex neuronal interactions and structural organization of different regions in the human brain. For investigating early onset of dementia and cortical atrophy, we generated cortical organoids as cortex is the primary brain region affected in neuro degenerative diseases. In addition to the wild-type DNMT1 organoids, we cultured heterozygous DNMT1-Y511C organoids to mimic the condition of the patient, and homozygous DNMT1-Y511C to understand how the mutation affects the cortical development and the compensatory mechanisms that might be taking place in the heterozygous model. In this study, we found that the heterozygous and homozygous were significantly smaller than the wild type organoids and the size was tracked till day 400. To understand why such significant size difference occurred in this mutation, we will evaluate the cortical atrophy in different developmental stages by immunostaining for NeuN and MAP2 to quantify neuron content and test if cortical atrophy is a result of overall neuron loss. Keywords: DNMT1; HSAN1E; Organoids; Neurodegeneration

Source:

Purdue University / 2024

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Co-authors:

Akila Abeyaratna