The Dr. Martin Rodbell Lecture Series Seminar for 2019 featured neuroscientist Susan Ackerman, Ph.D. professor of Cellular and Molecular Medicine at the University of California, San Diego. Ackerman’s talk described the genetic approach she and her research group use, which may shed light on common neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.

Ackerman uses inbred mouse strains in her studies to take advantage of their different genetic backgrounds. The various strains each tend to produce different observable characteristics, known as phenotypes. For example, one mouse strain could have a mutation that impairs muscle coordination, whereas another strain could carry a mutation that allows protein aggregates to form in neurons.

Ackerman’s talk was titled, 'Defects in mRNA Translation, Neurodegeneration, and Modifier Genes.' (Photo courtesy of Michael Garske)

Ackerman said these different phenotypes occur because modifier genes affect the consequences of mutations in specific target genes. By studying these processes in mice, she intends to identify and characterize novel pathways involved in regulation of neurodegeneration in the aging brain.

'Dr. Ackerman’s forward genetic approaches have elegantly defined how many genes affect neurological development and neurodegeneration,' said Rodbell Lecture host Robin Stanley, Ph.D., head of the NIEHS Nucleolar Integrity Group. 'Her work is significant because it lays the foundation for discovering cures for neurodegenerative diseases.'

Modifier genes

Ackerman gave an example, based on research from another group, of the effects of modifier genes on human disease. Retinitis pigmentosa (RP), which refers to a group of disorders involving the loss of cells in the retina, can be caused by a mutation on the X chromosome, so males are affected. In one family, a set of fraternal twins both had the mutation. One was diagnosed with RP at age 10 years, yet his brother did not develop the disease until age 52 years.

'We suggest that the modifier genes are segregating between patients, and even siblings, to change the expressivity or the phenotypic severity of disease,' Ackerman said. 'If we can identify modifier genes of disease, we could understand the relationship between the primary genetic defect and the disease, as well as make progress on developing possible therapies.'

Looking for modifier genes in humans is difficult because there are not large enough populations with these rare, genetic disorders to find associations with modifier genes. So, Ackerman and her colleagues use the naturally occurring variations in different inbred mouse strains (see sidebar).

At the genomic level, the mouse strains are super-divergent, having up to 35 million single nucleotide polymorphisms between strains and millions of insertions and deletions in the genetic code.

Neurodegeneration in mice

A few years ago, Ackerman was working on a spontaneous mouse mutant whose neurons developed a type of protein aggregate commonly found in neurodegenerative diseases, called ubiquitinated protein aggregates.

The animals, called sticky mutant mice, accumulated ubiquitinated aggregates in their Purkinje cells, located in the cerebellar cortex. Protein aggregates and neurodegeneration in sticky mutant mice occurred because of a mutation in the editing domain of an enzyme called alanyl-tRNA synthetase. Early loss of Purkinje cells happened at about 3 weeks of age, and by 4 months, almost all Purkinje cells in the mutant mouse strain were dead.

NIEHS Scientific Director Darryl Zeldin, M.D., left, and Stanley, right, presented Ackerman with the Rodbell Lecture statue. (Photo courtesy of Michael Garske)

Ackerman crossed this mutation into inbred mice with different backgrounds and found two genetic backgrounds that did not experience the neurodegeneration. Eventually, she found a novel protein called ANKRD16 that acts as a co-editor of tRNA synthetase.

'Dr. Ackerman’s work shows how even very closely related mouse strains can harbor significant genetic differences,' said Nick Plummer, Ph.D., staff scientist in the NIEHS Developmental Neurobiology Group. 'It is a reminder that we should pay close attention to the genetic background of our research animals.'