To determine the role of brain-derived neurotrophic factor (BDNF) in the enhancement of hippocampal neurogenesis resulting from dietary restriction (DR), heterozygous BDNF knockout (BDNF +/-) mice and wild-type mice were maintained for 3 months on DR or ad libitum (AL) diets. Mice were then injected with bromodeoxyuridine (BrdU) and killed either 1 day or 4 weeks later. Levels of BDNF protein in neurons throughout the hippocampus were decreased in BDNF +/-mice, but were increased by DR in wild-type mice and to a lesser amount in BDNF +/-mice. One day after BrdU injection the number of BrdU-labeled cells in the dentate gyrus of the hippocampus was significantly decreased in BDNF +/-mice maintained on the AL diet, suggesting that BDNF signaling is important for proliferation of neural stem cells. DR had no effect on the proliferation of neural stem cells in wild-type or BDNF +/-mice. Four weeks after BrdU injection, numbers of surviving labeled cells were decreased in BDNF +/-mice maintained on either AL or DR diets. DR significantly improved survival of newly generated cells in wild-type mice, and also improved their survival in BDNF +/-mice, albeit to a lesser extent. The majority of BrdU-labeled cells in the dentate gyrus exhibited a neuronal phenotype at the 4-week time point. The reduced neurogenesis in BDNF +/-mice was associated with a significant reduction in the volume of the dentate gyrus. These findings suggest that BDNF plays an important role in the regulation of the basal level of neurogenesis in dentate gyrus of adult mice, and that by promoting the survival of newly generated neurons BDNF contributes to the enhancement of neurogenesis induced by DR.

Summary Huntington’s disease (HD) is caused by an expanded CAG repeat in the Huntingtin (HTT) gene. The mechanism(s) by which mutant HTT (mHTT) causes disease is unclear. Nucleocytoplasmic transport, the trafficking of macromolecules between the nucleus and cytoplasm is tightly regulated by nuclear pore complexes (NPCs) made up of nucleoporins (NUPs). Previous studies offered clues that mHTT may disrupt nucleocytoplasmic transport and a mutation of a NUP can cause HD-like pathology. Therefore, we evaluated the NPC and nucleocytoplasmic transport in multiple models of HD including mouse and fly models, neurons transfected with mHTT, HD iPSC-derived neurons and human HD brain regions. These studies revealed severe mislocalization and aggregation of NUPs and defective nucleocytoplasmic transport. HD repeat-associated non-ATG (RAN) translation proteins also disrupted nucleocytoplasmic transport. Additionally, overexpression of NUPs and treatment with drugs that prevent aberrant NUP biology also mitigated this transport defect and neurotoxicity, providing future novel therapy targets.

In addition to neurological deficits, Huntington's disease (HD) patients and transgenic mice expressing mutant human huntingtin exhibit reduced levels of brain-derived neurotrophic factor, hyperglycemia, and tissue wasting. We show that the progression of neuropathological (formation of huntingtin inclusions and apoptotic protease activation), behavioral (motor dysfunction), and metabolic (glucose intolerance and tissue wasting) abnormalities in huntingtin mutant mice, an animal model of HD, are retarded when the mice are maintained on a dietary restriction (DR) feeding regimen resulting in an extension of their life span. DR increases levels of brain-derived neurotrophic factor and the protein chaperone heat-shock protein-70 in the striatum and cortex, which are depleted in HD mice fed a normal diet. The suppression of the pathogenic processes by DR in HD mice suggests that mutant huntingtin promotes neuronal degeneration by impairing cellular stress resistance, and that the body wasting in HD is driven by the neurodegenerative process. Our findings suggest a dietary intervention that may suppress the disease process and increase the life span of humans that carry the mutant huntingtin gene.is an inherited neurodegenerative disorder characterized by degeneration of neurons in the striatum and cerebral cortex resulting in abnormal involuntary movements (chorea), and psychiatric and cognitive abnormalities (1). The genetic defect involves expansion of CAG trinucleotide repeats in exon 1 of the HD gene resulting in polyglutamine expansions in the huntingtin protein (2-4). Neither the normal function of huntingtin nor the mechanism whereby polyglutamine expansions result in selective loss of striatal neurons is known, although impaired energy metabolism (5, 6), excitotoxicity (7), and oxidative stress (8) are implicated. It has been proposed that the mutant huntingtin causes neuronal dysfunction and death by altering the transcription of certain genes, including those encoding neurotransmitters and neurotrophic factors (9). Transgenic mice expressing polyglutamine expanded full-length or N-terminal fragments of huntingtin exhibit neurodegenerative changes in the striatum, progressive motor dysfunction, and premature death (10, 11). Oxidative stress and apoptosis are suggested in the pathogenic process because antioxidants (12) and caspase inhibitors (13) can slow disease progression in huntingtin mutant mice.Deficits in striatal and cortical glucose metabolism precede the appearance of symptoms in HD patients (14-16). Many HD patients and huntingtin mutant mice also exhibit hyperglycemia, apparently as the result of decreased insulin production and͞or sensitivity (17,18). A deficit in cellular energy metabolism may contribute to disease onset and progression because administration of creatine, an agent that reduces ATP depletion, delays the onset of symptoms and increases the survival times of huntingtin mutant mice (19). Another alteration in HD is decreased production of brain-derived neurotrophic factor (BDNF) (...