We have identified several growth factors and cytokines that can protect neurons against dysfunction and death in experimental models of Alzheimers disease, Parkinsons disease and stroke. These trophic factors activate signaling pathways that stimulate the expression of genes whose encoded proteins increase resistance of neurons to oxidative and metabolic stress. Neuroprotective Actions of BDNF. We have found that brain-derived neurotrophic factor (BDNF) is a key mediator of the neuroprotective effects of dietary restriction in animal models of Parkinsons and Huntingtons diseases. Parkinson's disease (PD) patients often exhibit impaired regulation of heart rate by the autonomic nervous system (ANS) that may precede motor symptoms in many cases. Results of autopsy studies suggest that brainstem pathology, including the accumulation of -synuclein, precedes damage to dopaminergic neurons in the substantia nigra in PD. However, the molecular and cellular mechanisms responsible for the early dysfunction of brainstem autonomic neurons are unknown. Here we report that mice expressing a mutant form of -synuclein that causes familial PD exhibit aberrant autonomic control of the heart characterized by elevated resting heart rate and an impaired cardiovascular stress response, associated with reduced parasympathetic activity and accumulation of -synuclein in the brainstem. These ANS abnormalities occur early in the disease process. Adverse effects of -synuclein on the control of heart rate are exacerbated by a high energy diet and ameliorated by intermittent energy restriction. Our findings establish a mouse model of early dysregulation of brainstem control of the cardiovascular system in PD, and further suggest the potential for energy restriction to attenuate ANS dysfunction, particularly in overweight individuals. The Sonic hedgehog (Shh) signaling pathway is well known in patterning of the neural tube during embryonic development, but its emerging role in differentiated neurons is less understood. Here we report that Shh enhances autophagy in cultured hippocampal neurons. Microarray analysis reveals the upregulation of multiple autophagy-related genes in neurons in response to Shh application. Through analysis of the autophagy-marker LC3 by immunoblot analysis and immunocytochemistry, we confirm activation of the autophagy pathway in Shh-exposed neurons. Using electron microscopy, we find autophagosomes and associated structures with a wide range of morphologies in synaptic terminals of Shh-exposed neurons. Moreover, we show that Shh-triggered autophagy depends on class III Phosphatidylinositol 3-kinase complexes (PtdIns3K). These results identify a link between Shh and autophagy pathways and, importantly, provide a lead for further understanding the physiology of Shh signaling activity in neurons. The formation, maintenance and reorganization of synapses are critical for brain development and the responses of neuronal circuits to environmental challenges. Here we describe a novel role for peroxisome proliferator-activated receptor; alpha co-activator PGC-1alpha;, a master regulator of mitochondrial biogenesis, in the formation and maintenance of dendritic spines in hippocampal neurons. In cultured hippocampal neurons, PGC-1alpha; overexpression increases dendritic spines and enhances the molecular differentiation of synapses, whereas knockdown of PGC-1alpha; inhibits spinogenesis and synaptogenesis. PGC-1alpha; knockdown also reduces the density of dendritic spines in hippocampal dentate granule neurons in vivo. We further show that brain-derived neurotrophic factor stimulates PGC-1alpha;-dependent mitochondrial biogenesis by activating extracellular signal-regulated kinases and cyclic AMP response element-binding protein. PGC-1alpha; knockdown inhibits brain-derived neurotrophic factor-induced dendritic spine formation without affecting expression and activation ofthe brain-derived neurotrophic factor receptor tyrosine receptor kinase B. Our findings suggest that PGC-1alpha; and mitochondrial biogenesis have important roles in the formation and maintenance of hippocampal dendritic spines and synapses. Based on our own research and evolutionary considerations, we developed a new hypothesis to explain the health benefits of plant consumption, namely, that some phytochemicals exert disease-preventive and therapeutic actions by engaging one or more adaptive cellular response pathways in cells. The evolutionary basis for this hypothesis is based on the fact that plants produce natural antifeedant/noxious chemicals that discourage insects and other organisms from eating them. However, in the amounts typically consumed by humans, the phytochemicals activate one or more conserved adaptive cellular stress response pathways and thereby enhance the ability of cells to resist injury and disease. Examples of such pathways include those involving stress-responsive transcription factors , as well as the production and action of trophic factors and hormones. Translational research to develop interventions that target these pathways may lead to new classes of therapeutic agents that act by stimulating adaptive stress response pathways to bolster endogenous defenses against brain injury and disease. The impact of mitochondrial protein acetylation status on neuronal function and vulnerability to neurological disorders is unknown. Here we show that the mitochondrial protein deacetylase SIRT3 mediates adaptive responses of neurons to bioenergetic, oxidative, and excitatory stress. Cortical neurons lacking SIRT3 exhibit heightened sensitivity to glutamate-induced calcium overload and excitotoxicity and oxidative and mitochondrial stress; AAV-mediated Sirt3 gene delivery restores neuronal stress resistance. In models relevant to Huntington's disease and epilepsy, Sirt3(-/-) mice exhibit increased vulnerability of striatal and hippocampal neurons, respectively. SIRT3 deficiency results in hyperacetylation of several mitochondrial proteins, including superoxide dismutase 2 and cyclophilin D. Running wheel exercise increases the expression of Sirt3 in hippocampal neurons, which is mediated by excitatory glutamatergic neurotransmission and is essential for mitochondrial protein acetylation homeostasis and the neuroprotective effects of running. Our findings suggest that SIRT3 plays pivotal roles in adaptive responses of neurons to physiological challenges and resistance to degeneration. The presence of Sonic Hedgehog (Shh) and its signaling components in the neurons of the hippocampus raises a question about what role the Shh signaling pathway may play in these neurons. We show here that activation of the Shh signaling pathway stimulates axon elongation in rat hippocampal neurons. This Shh-induced effect depends on the pathway transducer Smoothened (Smo) and the transcription factor Gli1. The axon itself does not respond directly to Shh; instead, the Shh signal transduction originates from the somatodendritic region of the neurons and occurs in neurons with and without detectable primary cilia. Upon Shh stimulation, Smo localization to dendrites increases significantly. Shh pathway activation results in increased levels of profilin1 (Pfn1), an actin-binding protein. Mutations in Pfn1's actin-binding sites or reduction of Pfn1 eliminate the Shh-induced axon elongation. These findings indicate that Shh can regulate axon growth, which may be critical for development of hippocampal neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000314-18
Application #
9770105
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Zhang, Shi; Eitan, Erez; Wu, Tsung-Yu et al. (2018) Intercellular transfer of pathogenic ?-synuclein by extracellular vesicles is induced by the lipid peroxidation product 4-hydroxynonenal. Neurobiol Aging 61:52-65
Connolly, Niamh M C; Theurey, Pierre; Adam-Vizi, Vera et al. (2018) Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases. Cell Death Differ 25:542-572
Mattson, Mark P; Arumugam, Thiruma V (2018) Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States. Cell Metab 27:1176-1199
Mattson, Mark P; Moehl, Keelin; Ghena, Nathaniel et al. (2018) Intermittent metabolic switching, neuroplasticity and brain health. Nat Rev Neurosci 19:63-80
Misiak, Magdalena; Vergara Greeno, Rebeca; Baptiste, Beverly A et al. (2017) DNA polymerase ? decrement triggers death of olfactory bulb cells and impairs olfaction in a mouse model of Alzheimer's disease. Aging Cell 16:162-172
Yao, Pamela J; Manor, Uri; Petralia, Ronald S et al. (2017) Sonic hedgehog pathway activation increases mitochondrial abundance and activity in hippocampal neurons. Mol Biol Cell 28:387-395
Geisler, John G; Marosi, Krisztina; Halpern, Joshua et al. (2017) DNP, mitochondrial uncoupling, and neuroprotection: A little dab'll do ya. Alzheimers Dement 13:582-591
Mattson, Mark P; Longo, Valter D; Harvie, Michelle (2017) Impact of intermittent fasting on health and disease processes. Ageing Res Rev 39:46-58
Zhang, Shi; Eitan, Erez; Mattson, Mark P (2017) Early involvement of lysosome dysfunction in the degeneration of cerebral cortical neurons caused by the lipid peroxidation product 4-hydroxynonenal. J Neurochem 140:941-954
Nigam, Saket M; Xu, Shaohua; Kritikou, Joanna S et al. (2017) Exercise and BDNF reduce A? production by enhancing ?-secretase processing of APP. J Neurochem 142:286-296

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