DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Deletion of Anaplastic Lymphoma Kinase improves cognitive impairments in a mouse model of Neurofibromatosis Type 1

Posted June 7, 2017
Jacob Raber, Ph.D., Oregon Health & Science University

Jacob Raber, Ph.D.
Jacob Raber, Ph.D.,
Oregon Health & Science University
Photo used with permission
of Dr. Raber

Neurofibromatosis 1 (NF1) is caused by mutations in the gene that encodes the protein neurofibromin. NF1 has many associated symptoms, the most commonly observed being cognitive impairment. There has also been some evidence of sleep disturbance in NF1 patients, but this is not well-studied. Other research groups have linked Anaplastic Lymphoma Kinase (Alk) to NF1 in fly models with regard to both sleep and cognitive function. These studies led Dr. Jacob Raber, of Oregon Health & Science University, and his colleagues – with funding from an NFRP Fiscal Year 2012 (FY12) Exploration - Hypothesis Development Award – to investigate the roles of Alk in these pathways in mice.

Dr. Raber hypothesized that a mouse model of NF1 (NF1 mice) lacking the Alk gene would perform better in tests of cognitive functions, such as spatial learning and memory, and have improved circadian activity levels compared to NF1 mice with the Alk gene. NF1 mice lacking either one or both copies of their Alk gene performed better in tests of spatial learning and memory than NF1 mice with both copies of the Alk gene. Furthermore, data from preliminary studies suggest that lack of Alk in NF1 mice improves circadian activity levels, as NF1 mice with both copies of the Alk gene are less active than NF1 mice without one or both copies of the Alk gene. These results point to Alk as a potential therapeutic target in NF1.

Dr. Raber and his colleagues were recently awarded an FY16 Investigator-Initiated Research Award to continue this research. They will be evaluating potential benefits and adverse effects of a pharmacological Alk inhibitor in NF1 mice. These studies could lay the foundation for pursuing Alk inhibition as a treatment of behavioral and cognitive impairments in NF1 patients.

Publication:

Weiss JB, Weber SJ, Torres ES, Marzulla T, and Raber J. 2017. Genetic inhibition of Anaplastic Lymphoma Kinase rescues cognitive impairments in Neurofibromatosis 1 mutant mice. Behav Brain Res 321:148–156.

Link:

Public and Technical Abstracts: Effects of Pharmacologic and Genetic Inhibition of Alk on Cognitive Impairments in NF1 Mutant Mice

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Last updated Wednesday, June 7, 2017