DYNAMICS OF THE NEURONAL CYTOSKELETON IN AGING BRAIN
Principal Investigator: Ralph A Nixon
Abstract: DESCRIPTION (provided by applicant): Neurofilaments (NF) enable axons to achieve the large calibers required for normal nerve impulse conduction and play other critical roles in neuronal function only now being appreciated. In several major neurodegenerative diseases, including a form of fronto-temporal dementia, abnormal accumulations of NF are a neuropathologic hallmark believed to contribute to neuronal dysfunction. Indeed, the association of NF gene mutations with Charcot Marie Tooth type 2E/1F neuronopathy and with early-onset Parkinson's disease (PD) unequivocally implicates NF directly in neurodegenerative disease pathogenesis. Our studies in the past grant term revealed new fundamental properties of NF and suggested a novel function for NF as a scaffold in axons and synapses, which reversibly docks vesicular organelles and proteins, including neurotransmitter receptors, and thereby may regulate their function. We identified the middle subunit of NF (NFM) as uniquely crucial for NF transport and key NF scaffold functions. We propose to test hypotheses, based on preliminary data, that the head and rod domains of NFM regulate NF transport and trigger NF network formation along axons. By replacing endogenous NFM in neurons with genetically modified and truncated forms of NFM, we propose to define roles of the head and rod domains, including head phosphorylation, and the effects on NF behavior of a NFM mutation associated with severe PD (aims 1a-d). Studies will be performed in primary neuronal cultures using videomicroscopy and in retinal ganglion cells in vivo by established radiolabeling and ultrastructural methods, exploiting the previously successful approach we used to define functions of NF carboxyl- tail domains. Having pinpointed NFM rod as the likely binding site for NF motors, we will perform genetic screens to identify putative NF motor(s) (aim 1e). Based on new findings that NFM and the D1 dopamine receptor (D1R) interact functionally to modulate D1R -mediated behaviors in vivo, we will test the hypothesis that D1R docking to a NFM-containing scaffold influences endocytic recycling of D1R to synaptic membranes and thus sensitivity to DA agonists (aim 2). We will characterize D1R recycling in striatal primary neurons of mice with NFM deletion or related alterations and will ultrastructurally and biochemically localize D1R-NFM interaction sites within neurons in vivo. Finally, we will clarify the poorly understood role of proteolysis in regulating NF accumulation and NF network stability and its modulation by NF structural properties as a basis for understanding pathological NF accumulation in neurological diseases and brain aging (aim 3). Novel approaches to alter the in vivo activities of three major proteolytic systems implicated by our preliminary data and protease modulations in primary neurons will be used. These studies address fundamental aspects of NF biology related to the normal functions of axons and synapses and are directly relevant to mechanisms of neuroaxonal degeneration in neurofibrillary diseases, including Alzheimer's disease and related dementias, amyotrophic lateral sclerosis and related neuronopathies, Parkinson's disease and glaucoma. PUBLIC HEALTH RELEVANCE: This project addresses how neurons assemble an internal supporting framework enabling them to connect and communicate with other neurons. The regulation of this process controls important neuron functions and is known to be disrupted in neurodegenerative diseases associated with aging. Defining the specific steps in this regulation will help to clarify mechanisms leading to major neurological diseases, including dementias, and will identify novel cellular targets for developing innovative therapies for these diseases.
Funding Period: 1985-09-30 - 2015-05-31
more information: NIH RePORT
- Axonal transport rates in vivo are unaffected by tau deletion or overexpression in miceAidong Yuan
Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York 10962, USA
J Neurosci 28:1682-7. 2008..These results suggest that tau is not essential for axonal transport and that transport rates in vivo are not significantly affected by substantial fluctuations in tau expression...
- Lysosome and calcium dysregulation in Alzheimer's disease: partners in crimeMarykate McBrayer
Center for Dementia Research, Nathan S Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, U S A
Biochem Soc Trans 41:1495-502. 2013..In the present review, we discuss the close inter-relationships among deficits of lysosomal function, autophagy and Ca2+ homoeostasis as a pathogenic process in PS1-related FAD and their relevance to sporadic AD. ..
- Global axonal transport rates are unaltered in htau mice in vivoAidong Yuan
Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA Department of Psychiatry, New York University School of Medicine, NY, USA
J Alzheimers Dis 37:579-86. 2013..These studies demonstrate that human tau overexpression, even when associated with a limited degree of tau pathology, does not necessarily impair general axonal transport function in vivo. ..
- The role of autophagy in neurodegenerative diseaseRalph A Nixon
Center for Dementia Research, Nathan S Kline Institute, Orangeburg, New York, USA
Nat Med 19:983-97. 2013..Various therapeutic strategies for modulating specific stages of autophagy and the current state of drug development for this purpose are also evaluated. ..
- The C-terminal domains of NF-H and NF-M subunits maintain axonal neurofilament content by blocking turnover of the stationary neurofilament networkMala V Rao
Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York, United States of America
PLoS ONE 7:e44320. 2012....
- The myosin Va head domain binds to the neurofilament-L rod and modulates endoplasmic reticulum (ER) content and distribution within axonsMala V Rao
Nathan Kline Institute, New York University School of Medicine, Orangeburg, New York, United States of America
PLoS ONE 6:e17087. 2011..Based on observations that the Myo Va motor domain binds to intermediate filament (IF) proteins of several classes, Myo Va interactions with IFs may serve similar roles in organizing organelle topography in different cell types...
- The contributions of myelin and axonal caliber to transverse relaxation time in shiverer and neurofilament-deficient mouse modelsVictor V Dyakin
Center for Dementia Research, Nathan Kline Institute Orangeburg, New York 10962, USA
Neuroimage 51:1098-105. 2010..Our findings indicate that T2 is strongly influenced by myelination state and axonal volume, while neurofilament structure within the intra-axonal compartment has a lesser effect upon single compartment T2 estimates...
- Declining phosphatases underlie aging-related hyperphosphorylation of neurofilaments- Veeranna
Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, United States Department of Psychiatry, New York University School of Medicine, New York, NY 10016, United States
Neurobiol Aging 32:2016-29. 2011..Declining PP2A activity, therefore, can account for rising neurofilament phosphorylation in maturing brain, potentially compounding similar changes associated with adult-onset neurodegenerative diseases...
- Neurofilaments form a highly stable stationary cytoskeleton after reaching a critical level in axonsAidong Yuan
Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York 10962, USA
J Neurosci 29:11316-29. 2009..These findings reconcile in vitro and in vivo axonal transport observations, showing that slowly transported NFs or subunit oligomers are precursors to a highly stable stationary cytoskeletal network that supports mature axons...
- Marked calpastatin (CAST) depletion in Alzheimer's disease accelerates cytoskeleton disruption and neurodegeneration: neuroprotection by CAST overexpressionMala V Rao
Center for Dementia Research, Nathan S Kline Institute, Orangeburg, New York 10962, USA
J Neurosci 28:12241-54. 2008..CAST mimetics may, therefore, be neuroprotective in AD...
- Neurofilament tail phosphorylation: identity of the RT-97 phosphoepitope and regulation in neurons by cross-talk among proline-directed kinases- Veeranna
Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA
J Neurochem 107:35-49. 2008..The regulation of a single target by multiple protein kinases underscores the importance of monitoring other relevant kinases when the activity of a particular one is blocked...
- Dystrophic serotonergic axons in neurodegenerative diseasesEfrain C Azmitia
Department of Biology and Center for Neural Science, New York, New York 10003, USA
Brain Res 1217:185-94. 2008..This is the first report of dystrophic 5-HTT-IR axons in postmortem human tissue...
- Overexpression of the calpain-specific inhibitor calpastatin reduces human alpha-Synuclein processing, aggregation and synaptic impairment in [A30P]αSyn transgenic miceMeike Diepenbroek
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen 72076, Germany
Hum Mol Genet 23:3975-89. 2014..Overall, our data further support a crucial role of calpains, particularly of calpain 1, in the pathogenesis of PD and in disease-associated aggregation of αSyn, indicating a therapeutic potential of calpain inhibition in PD. ..
- Injury and Recovery in Developing BrainFlora M Vaccarino; Fiscal Year: 2013..The long-term goal of these studies is to identify new means of therapeutic intervention to decrease the developmental disability and neurobehavioral sequelae of preterm birth. ..
- UNMC EPPLEY CANCER CENTER SUPPORT GRANTKenneth H Cowan; Fiscal Year: 2013....
- Molecular motors in cell biologyYale E Goldman; Fiscal Year: 2013..We anticipate that the proposed work will take us significantly further toward our goal of understanding motility in the normal and pathological function of cells. ..
- Genetic analyses of axon transport and microtubule dynamics in ZebrafishAlex Nechiporuk; Fiscal Year: 2013....
- Protein Dynamics in Enzymatic CatalysisRobert Callender; Fiscal Year: 2013..The Equipment Core (Core A) supports the specialized comprehensive suite of instrumentation for the Program. The Administrative Core (Core B) administers the Program Project. ..
- TBI-Induced Cerebral Metabolic Depression and RecoveryDavid A Hovda; Fiscal Year: 2013..This program project will be housed within the UCLA Brain Injury Research Center (Dr. David A. Hovda, Director) so as to assure appropriate imaging, administrative and laboratory support. ..
- Emory Alzheimer's Disease CenterAllan I Levey; Fiscal Year: 2013..abstract_text> ..
- Assembly and Axonal Transport of NeurofilamentsAnthony Brown; Fiscal Year: 2013..The mechanisms that regulate neurofilament pausing are likely targets for disease processes that lead to excessive accumulation of neurofilaments in axons. ..
- Regulation of synaptic proteasome activity by the dynactin complexBENJAMIN ARTHUR EATON; Fiscal Year: 2013..We predict that studies aimed at elucidating the molecular mechanism associated with the regulation of synapse maintenance will have broad applications to neurological disease and provide the basis for novel strategies for treatment. ..
- Expanding the National Health AccountsDavid M Cutler; Fiscal Year: 2013..Establishment of a set of national health accounts will allow us as a society to understand which medical interventions improve the health of the U.S. population most efficiently. ..
- Engineering inhibitable kinesin motors to study axonal transportKristen J Verhey; Fiscal Year: 2013..This work will provide exciting new insights into how kinesin motors give rise to coordinated transport of protein complexes in cells and will suggest therapeutic targets in human disease. ..
- Molecular Mechanisms linking Aging, Abeta Proteotoxicity and NeurodegenerationJeffery W Kelly; Fiscal Year: 2013..abstract_text> ..
- Signaling of Endothelial Permeability and Lung Vascular InjuryAsrar B Malik; Fiscal Year: 2013..Moreover the depth of understanding to be gained of the signaling pathways mediating the increase in lung vascular permeability will provide novel insights into the mechanisms of protein-rich pulmonary edema and ARDS. ..
- EINSTEIN AGING STUDYRichard B Lipton; Fiscal Year: 2013..Together, these Projects will help disentangle the multifactorial processes that lead to cognitive and locomotor decline and dementia. ..
- Alerations of Sleep and Circadian Timing in AgingEve Van Cauter; Fiscal Year: 2013..Core B (Methods and Analysis) will standard operating procedures for data collection, archival and analysis. Core C will assay peripheral levels of hormones, cytokines and other blood constituents. ..
- Alzheimer's Disease Research CenterOscar L Lopez; Fiscal Year: 2013..Alzheimer's centers such as the one in Pittsburgh play a critical role in the nation's struggle to: 1) care for those currently afflicted;2) improve diagnosis and treatment;and 3) find a means of prevention. ..
- Alzheimer's Disease Research CenterDouglas R Galasko; Fiscal Year: 2013..It will provide an environment and core resources to enhance research, foster professional and community training, and coordinate interdisciplinary research. ..
- UCLA Alzheimer's Disease Research CenterDavid B Teplow; Fiscal Year: 2013..Innovations in advancing research are proposed in each Core of this proposal. Each core has responded to criticisms and recommendations from the 2008 review in this renewal application. ..
- Alpha-synuclein degradation mechanismsJianhua Zhang; Fiscal Year: 2013..Our work will determine the function of the autophagy-lysosomal pathway in reducing a-syn level and toxicity, a strategy relevant to improving treatment of PD and other a-synucleinopathies. ..
- Neuronal Cell Cycle and SurvivalNicholas E Baker; Fiscal Year: 2013....