Several lines of evidence indicate an association between mitochondrial DNA (mtDNA) and the functioning of the nervous system. As neuronal development and structure as well as axonal and synaptic activity involve mitochondrial genes, it is not surprising that most mtDNA diseases are associated with brain disorders. Only one study has suggested an association between mtDNA and cognition, however. Here we provide direct evidence of mtDNA involvement in cognitive functioning. Total substitution of mtDNA was achieved by 20 repeated backcrosses in NZB/BlNJ (N) and CBA/H (H) mice with different mtDNA origins. All 13 mitochondrial genes were expressed in the brains of the congenic quartet. In interaction with nuclear DNA (nDNA), mtDNA modified learning, exploration, sensory development and the anatomy of the brain. The effects of mtDNA substitution persisted with age, increasing in magnitude as the mice got older. We observed different effects with input of mtDNA from N versus H mice, varying according to the phenotypes. Exchanges of mtDNA may produce phenotypes outside the range of scores observed in the original mitochondrial and nuclear combinations. These findings show that mitochondrial polymorphisms are not as neutral as was previously believed.

Neurofibromin is a large and multifunctional protein encoded by the tumor suppressor gene NF1, mutations of which cause the tumor predisposition syndrome neurofibromatosis type 1 (NF1). Over the last three decades, studies of neurofibromin structure, interacting partners, and functions have shown that it is involved in several cell signaling pathways, including the Ras/MAPK, Akt/mTOR, ROCK/LIMK/cofilin, and cAMP/PKA pathways, and regulates many fundamental cellular processes, such as proliferation and migration, cytoskeletal dynamics, neurite outgrowth, dendritic-spine density, and dopamine levels. The crystallographic structure has been resolved for two of its functional domains, GRD (GAP-related (GTPase-activating protein) domain) and SecPH, and its post-translational modifications studied, showing it to be localized to several cell compartments. These findings have been of particular interest in the identification of many therapeutic targets and in the proposal of various therapeutic strategies to treat the symptoms of NF1. In this review, we provide an overview of the literature on neurofibromin structure, function, interactions, and regulation and highlight the relationships between them.