Neuronatin gene: Imprinted and misfolded. Studies in Lafora disease, diabetes and cancer may implicate NNAT-aggregates as a common downstream participant in neuronal loss

摘要

Neuronatin (NNAT) is a ubiquitous and highly conserved mammalian gene involved in brain development. Its mRNA isoforms, chromosomal location, genomic DNA structure and regulation have been characterized. More recently there has been rapid progress in the understanding of its function in physiology and human disease. In particular there is fairly direct evidence implicating neuronatin in the causation of Lafora disease and diabetes. Neuronatin protein has a strong predisposition to misfold and form cellular aggregates that cause cell death by apoptosis. Aggregation of Neuronatin within cortical neurons and resulting cell death is the hallmark of Lafora disease, a progressive and fatal neurodegenerative disease. Under high glucose conditions simulating diabetes, neuronatin protein also accumulates and destroys pancreatic beta cells.The neuronatin gene is imprinted and only the paternal allele is normally expressed in the adult. However, changes in DNA methylation may cause the maternal allele to lose imprinting and trigger cell proliferation and metastasis. Neuronatin has also been shown to be translated peripherally within the dendrites of neurons, a finding of relevance in synaptic plasticity. The current understanding of the function of neuronatin raises the possibility that this gene may participate in the common downstream mechanisms associated with aberrant neuronal growth and death. A better understanding of these mechanisms may open new therapeutic targets to help modify the progression of devastating neurodegenerative conditions such as Alzheimer's and anterior horn cell disease.