The Neurology Department aims for the highest quality of clinical care, the best training experience for our medical students, residents and Fellows, and the performance of cutting-edge research.


This collection contains the scholarly works of faculty in the Department of Neurology.

Recent Submissions

  • Mechanisms of Estrogen Neuroprotection in Stroke

    Raz, Limor; Department of Neurology (2011-04)
    17-β estradiol (17-β-E2) has been implicated to be neuroprotective, yet the mechanisms underlying 17-β-E2-mediated protection against stroke remain unclear. The purpose of the current study was to elucidate the role of 17-β-E2 in NADPH oxidase (NOX2) activation during ischemic reperfusion induction of superoxide (O2 -) in the hippocampus CA1 region following global cerebral ischemia (GCI) and to investigate the post-translational deacetylation of downstream pro-apoptotic factors by 17-β-E2. Using a 4-vessel occlusion model to induce GCI, we showed that neuronal NOX2 localizes to the membrane and that NADPH oxidase activity and O2 - production were rapidly and markedly attenuated by 17-β-E2 following reperfusion, in an estrogen receptor-dependent manner. Inhibition of NADPH oxidase activation via icv administration of a NOX2 competitive inhibitor, gp91ds-tat, strongly attenuated O2 - production and was neuroprotective. The increase of neuronal NOX2 and O2 - following cerebral ischemia was shown to require Rac1 activation, as administration of a Rac1 inhibitor (NSC23766) significantly attenuated these factors following stroke. Interestingly, we found that 17-β-E2 antioxidant ability to diminish neuronal NOX2-induced O2 - generation involves the attenuation of Rac1 activation. We also provide evidence for 17-β-E2 post-translational deacetylation of downstream pro-apoptotic p53 and a reduction of p53 transcriptional target, Puma. Our results revealed that p53 acetylation (activation) is markedly increased in ischemic animals 24h after reperfusion and that 17-β-E2 strongly attenuated that elevation, as well as total p53 protein levels. In support of this suggestion, we also found 17-β-E2 to strongly attenuate ischemia-mediated Puma upregulation, thus interfering with its transcription-dependent function. We further propose that 17-β-E2-induced attenuation of p53 levels may involve an upregulation in p53-Mdm2 interactions and p53 mediated degradation via the ubiquitination pathway. Lastly, we provide evidence showing that treatment with Gp91ds-tat, but not the scrambled tat peptide control, attenuated acetylation of downstream p53 and reduced levels of Puma, thus supporting O2 —p53 crosstalk signaling after stroke. Altogether, our studies reveal a novel, membrane-mediated antioxidant mechanism of 17-β-E2-induced neuroprotection via reduction of neuronal NOX2 activation and O2 - production, while providing evidence for 17-β-E2–mediated deacetylation and inactivation of p53, thereby protecting the hippocampus CA1 against cerebral ischemia.
  • Structure-Functional Relationship Study of Glycosyltransferases

    Gu, Yihua; Department of Neurology (2008-05)
    Gangliosides are a group of functional molecules and are synthesized by glycosyltransferases in a stepwise manner. Mechanism of ganglioside profile change in normal conditions or in diseases is not well understood. Gene regulations, protein structures and catalytic mechanisms of related glycosyltransferases may provide clues to elucidate this phenomenon. In our project, GD3-synthase is used as a model of glycosyltransferases for protein structure-functional relationship study. GD3-synthase is a key enzyme in the ganglioside biosynthetic network. It catalyzes the biosynthesis of ganglioside GD3, which is the entry substrate of biosynthesis of the b- and c- series gangliosides. GD3 is a minor ganglioside in adult vertebrate tissues, while it is highly expressed during embryonic development and in pathological conditions, such as cancer. GD3 is also involved in aging, cell proliferation, and cell differentiation. Aspects that are still poorly understood include: 1) the regulatory mechanisms for change of GD3 levels in normal condition and in diseases, 2) the structure of GD3-synthase, 3) how the structure is related to function, and 4) how the synthesis and degradation of the enzyme are regulated. To carry out the structure-functional relationship study on GD3-synthase, we developed a strategy to obtain a large amount of pure human GD3-synthase for crystallographic analysis. E. coli, yeast, and baculovirus systems were screened for selection of the expression system. Transmembrane domain-truncated human GD3-synthase was expressed in E. coli, but it aggregated into inclusion bodies. The refolded protein did not have enzyme activity. Human GD3-synthase could not be expressed in yeast cells, due to the presence of two yeast-specific stop codons. Although codon optimization was performed, the protein still could not be expressed in yeast cells. The soluble human GD3-synthase with enzymatic activity was expressed in Trichoplusia ni (T. ni) insect cells and secreted into the culture medium. The recombinant protein was purified from the culture medium with a yield of 1.45 mg/L. This is the first report of a procedure for expression and purification of GD3-synthase with a high yield, since the cDNA sequence was determined in 1994. As an alternative strategy, protein modeling was performed to study the structure-functional relationship of GD3-synthase. CstII, a bacterial sialyltransferase, was identified as a remote homologue of human GD3-synthase with a low sequence similarity. CstII and vertebrate sialyltransferases share a similar topology of protein structure, which makes it possible to build the structure of human GD3-synthase by using homology modeling. Sequence comparison (including primary sequence and secondary structure alignments) between CstII and human GD3-synthase was performed to identify the possible functional sites. Between sialylmotifs L and S, four highly conserved amino acid residues (Asn188, Pro189, Ser190, and Arg272) were identified. Protein sequence alignment of human sialyltransferases suggests that all conserved residues identified in our study are ST8Sia subfamily-specific. Functional analysis of these residues in human GD3-synthase was performed by using site-directed mutational analysis. Mutational analysis of these conserved residues suggests that Asn188, Ser190, and Arg272 are necessary for enzyme activity. The predicted 3-D structures of human GD3-synthase with docking of substrates support the data of mutational analysis and elucidate the contributions of these residues to the enzymatic activity, which suggests: 1) Asn188 is acceptor binding-related, 2) Ser190 functions to lock the acceptor substrate, and 3) Arg272 is acceptor binding-related. We also suggest that the protein modeling approach can be applied to structure-functional relationship studies only for those regions, which are highly conserved between vertebrate sialyltransferases and CstI/CstII, due to the low sequence similarity.
  • Focusing on Attention: The Effects of Working Memory Capacity and Load on Selective Attention

    Ahmed, Lubna; de Fockert, Jan W.; Tsien, Joe Z.; Department of Neurology; College of Graduate Studies (2012-08-28)
    Background: Working memory (WM) is imperative for effective selective attention. Distractibility is greater under conditions of high (vs. low) concurrent working memory load (WML), and in individuals with low (vs. high) working memory capacity (WMC). In the current experiments, we recorded the flanker task performance of individuals with high and low WMC during low and high WML, to investigate the combined effect of WML and WMC on selective attention.
  • Single-Channel Electrophysiology Reveals a Distinct and Uniform Pore Complex Formed by α-Synuclein Oligomers in Lipid Membranes

    Schmidt, Felix; Levin, Johannes; Kamp, Frits; Kretzschmar, Hans; Giese, Armin; Botzel, Kai; Tsien, Joe Z.; Department of Neurology; College of Graduate Studies (2012-08-3)
    Synucleinopathies such as Parkinson's disease, multiple system atrophy and dementia with Lewy bodies are characterized by deposition of aggregated α-synuclein. Recent findings indicate that pathological oligomers rather than fibrillar aggregates may represent the main toxic protein species. It has been shown that α-synuclein oligomers can increase the conductance of lipid bilayers and, in cell-culture, lead to calcium dyshomeostasis and cell death. In this study, employing a setup for single-channel electrophysiology, we found that addition of iron-induced α-synuclein oligomers resulted in quantized and stepwise increases in bilayer conductance indicating insertion of distinct transmembrane pores. These pores switched between open and closed states depending on clamped voltage revealing a single-pore conductance comparable to that of bacterial porins. Pore conductance was dependent on transmembrane potential and the available cation. The pores stably inserted into the bilayer and could not be removed by buffer exchange. Pore formation could be inhibited by co-incubation with the aggregation inhibitor baicalein. Our findings indicate that iron-induced α-synuclein oligomers can form a uniform and distinct pore species with characteristic electrophysiological properties. Pore formation could be a critical event in the pathogenesis of synucleinopathies and provide a novel structural target for disease-modifying therapy.
  • Diagnostic Potential of the NMDA Receptor Peptide Assay for Acute Ischemic Stroke

    Dambinova, Svetlana A.; Bettermann, Kerstin; Glynn, Theodore; Tews, Matthew; Olson, David; Weissman, Joseph D.; Sowell, Richard L.; Department of Neurology (2012-07-27)
    Background: The acute assessment of patients with suspected ischemic stroke remains challenging. The use of brain biomarker assays may improve the early diagnosis of ischemic stroke. The main goal of the study was to evaluate whether the NR2 peptide, a product of the proteolytic degradation of N-methyl-D-aspartate (NMDA) receptors, can differentiate acute ischemic stroke (IS) from stroke mimics and persons with vascular risk factors/healthy controls. A possible correlation between biomarker values and lesion sizes was investigated as the secondary objective.
  • Effects of Kisspeptin1 on Electrical Activity of an Extrahypothalamic Population of Gonadotropin-Releasing Hormone Neurons in Medaka (Oryzias latipes)

    Zhao, Yali; Wayne, Nancy L.; Brann, Darrell W; Department of Neurology; College of Graduate Studies (2012-05-23)
    Kisspeptin (product of the kiss1 gene) is the most potent known activator of the hypothalamo-pituitary-gonadal axis. Both kiss1 and the kisspeptin receptor are highly expressed in the hypothalamus of vertebrates, and low doses of kisspeptin have a robust and long-lasting stimulatory effect on the rate of action potential firing of hypophysiotropic gonadotropin releasing hormone-1 (GnRH1) neurons in mice. Fish have multiple populations of GnRH neurons distinguished by their location in the brain and the GnRH gene that they express. GnRH3 neurons located in the terminal nerve (TN) associated with the olfactory bulb are neuromodulatory and do not play a direct role in regulating pituitary-gonadal function. In medaka fish, the electrical activity of TN-GnRH3 neurons is modulated by visual cues from conspecifics, and is thought to act as a transmitter of information from the external environment to the central nervous system. TN-GnRH3 neurons also play a role in sexual motivation and arousal states, making them an important population of neurons to study for understanding coordination of complex behaviors. We investigated the role of kisspeptin in regulating electrical activity of TN-GnRH3 neurons in adult medaka. Using electrophysiology in an intact brain preparation, we show that a relatively brief treatment with 100 nM of kisspeptin had a long-lasting stimulatory effect on the electrical activity of an extrahypothalamic population of GnRH neurons. Dose-response analysis suggests a relatively narrow activational range of this neuropeptide. Further, blocking action potential firing with tetrodotoxin and blocking synaptic transmission with a low Ca2+/high Mg2+ solution inhibited the stimulatory action of kisspeptin on electrical activity, indicating that kisspeptin is acting indirectly through synaptic regulation to excite TN-GnRH3 neurons. Our findings provide a new perspective on kisspeptin's broader functions within the central nervous system, through its regulation of an extrahypothalamic population of GnRH neurons involved in multiple neuromodulatory functions.
  • Wnt proteins regulate acetylcholine receptor clustering in muscle cells

    Zhang, Bin; Liang, Chuan; Bates, Ryan; Yin, Yiming; Xiong, Wen-Cheng; Mei, Lin; Department of Neurology; Institute of Molecular Medicine and Genetics (2012-02-6)
    Background: The neuromuscular junction (NMJ) is a cholinergic synapse that rapidly conveys signals from motoneurons to muscle cells and exhibits a high degree of subcellular specialization characteristic of chemical synapses. NMJ formation requires agrin and its coreceptors LRP4 and MuSK. Increasing evidence indicates that Wnt signaling regulates NMJ formation in Drosophila, C. elegans and zebrafish.
  • Critical Role of NADPH Oxidase in Neuronal Oxidative Damage and Microglia Activation following Traumatic Brain Injury

    Zhang, Quan-Guang; Laird, Melissa D; Han, Dong; Nguyen, Khoi; Scott, Erin L.; Dong, Yan; Dhandapani, Krishnan M.; Brann, Darrell W; Department of Neurology; Institute of Molecular Medicine and Genetics; et al. (2012-04-2)
    Background: Oxidative stress is known to play an important role in the pathology of traumatic brain injury. Mitochondria are thought to be the major source of the damaging reactive oxygen species (ROS) following TBI. However, recent work has revealed that the membrane, via the enzyme NADPH oxidase can also generate the superoxide radical (O2^-), and thereby potentially contribute to the oxidative stress following TBI. The current study thus addressed the potential role of NADPH oxidase in TBI.
  • Sex-independent neuroprotection with minocycline after experimental thromboembolic stroke

    Hoda, Md Nasrul; Li, Weiguo; Ahmad, Ajmal; Ogbi, Safia; Zemskova, Marina A; Johnson, Maribeth H.; Ergul, Adviye; Hill, William D; Hess, David C.; Sazonova, Irina Y; et al. (2011-12-16)
    Background: Minocycline provides neurovascular protection reducing acute cerebral injury. However, it is unclear whether minocycline is effective in females. We tested minocycline in both sexes and aged animals using a novel embolic stroke model in mice that closely mimics acute thromboembolic stroke in humans.
  • a-Calcium Calmodulin Kinase II Modulates the Temporal Structure of Hippocampal Bursting Patterns

    Cho, Jeiwon; Bhatt, Rushi; Elgersma, Ype; Silva, Alcino J.; Tsien, Joe Z.; Department of Neurology; College of Graduate Studies (2012-02-20)
    The alpha calcium calmodulin kinase II (a-CaMKII) is known to play a key role in CA1/CA3 synaptic plasticity, hippocampal place cell stability and spatial learning. Additionally, there is evidence from hippocampal electrophysiological slice studies that this kinase has a role in regulating ion channels that control neuronal excitability. Here, we report in vivo single unit studies, with a-CaMKII mutant mice, in which threonine 305 was replaced with an aspartate (a-CaMKIIT305D mutants), that indicate that this kinase modulates spike patterns in hippocampal pyramidal neurons. Previous studies showed that a- CaMKIIT305D mutants have abnormalities in both hippocampal LTP and hippocampal-dependent learning. We found that besides decreased place cell stability, which could be caused by their LTP impairments, the hippocampal CA1 spike patterns of a-CaMKIIT305D mutants were profoundly abnormal. Although overall firing rate, and overall burst frequency were not significantly altered in these mutants, inter-burst intervals, mean number of intra-burst spikes, ratio of intra-burst spikes to total spikes, and mean intra-burst intervals were significantly altered. In particular, the intra burst intervals of place cells in a- CaMKIIT305D mutants showed higher variability than controls. These results provide in vivo evidence that besides its wellknown function in synaptic plasticity, a-CaMKII, and in particular its inhibitory phosphorylation at threonine 305, also have a role in shaping the temporal structure of hippocampal burst patterns. These results suggest that some of the molecular processes involved in acquiring information may also shape the patterns used to encode this information.
  • Lactate Produced by Glycogenolysis in Astrocytes Regulates Memory Processing

    Newman, Lori A.; Korol, Donna L.; Gold, Paul E.; Brann, Darrell W; Department of Neurology; College of Graduate Studies (2011-12-13)
    When administered either systemically or centrally, glucose is a potent enhancer of memory processes. Measures of glucose levels in extracellular fluid in the rat hippocampus during memory tests reveal that these levels are dynamic, decreasing in response to memory tasks and loads; exogenous glucose blocks these decreases and enhances memory. The present experiments test the hypothesis that glucose enhancement of memory is mediated by glycogen storage and then metabolism to lactate in astrocytes, which provide lactate to neurons as an energy substrate. Sensitive bioprobes were used to measure brain glucose and lactate levels in 1-sec samples. Extracellular glucose decreased and lactate increased while rats performed a spatial working memory task. Intrahippocampal infusions of lactate enhanced memory in this task. In addition, pharmacological inhibition of astrocytic glycogenolysis impaired memory and this impairment was reversed by administration of lactate or glucose, both of which can provide lactate to neurons in the absence of glycogenolysis. Pharmacological block of the monocarboxylate transporter responsible for lactate uptake into neurons also impaired memory and this impairment was not reversed by either glucose or lactate. These findings support the view that astrocytes regulate memory formation by controlling the provision of lactate to support neuronal functions.
  • Lowe Syndrome Protein OCRL1 Supports Maturation of Polarized Epithelial Cells

    Grieve, Adam G.; Daniels, Rachel D.; Sanchez-Heras, Elena; Hayes, Matthew J.; Moss, Stephen E.; Matter, Karl; Lowe, Martin; Levine, Timothy P.; Department of Neurology; College of Graduate Studies (2011-08-25)
    Mutations in the inositol polyphosphate 5-phosphatase OCRL1 cause Lowe Syndrome, leading to cataracts, mental retardation and renal failure. We noted that cell types affected in Lowe Syndrome are highly polarized, and therefore we studied OCRL1 in epithelial cells as they mature from isolated individual cells into polarized sheets and cysts with extensive communication between neighbouring cells. We show that a proportion of OCRL1 targets intercellular junctions at the early stages of their formation, co-localizing both with adherens junctional components and with tight junctional components. Correlating with this distribution, OCRL1 forms complexes with junctional components a-catenin and zonula occludens (ZO)-1/2/3. Depletion of OCRL1 in epithelial cells growing as a sheet inhibits maturation; cells remain flat, fail to polarize apical markers and also show reduced proliferation. The effect on shape is reverted by re-expressed OCRL1 and requires the 5'-phosphatase domain, indicating that down-regulation of 5-phosphorylated inositides is necessary for epithelial development. The effect of OCRL1 in epithelial maturation is seen more strongly in 3-dimensional cultures, where epithelial cells lacking OCRL1 not only fail to form a central lumen, but also do not have the correct intracellular distribution of ZO-1, suggesting that OCRL1 functions early in the maturation of intercellular junctions when cells grow as cysts. A role of OCRL1 in junctions of polarized cells may explain the pattern of organs affected in Lowe Syndrome.
  • Overt Attention and Context Factors: The Impact of Repeated Presentations, Image Type, and Individual Motivation

    Kaspar, Kai; König, Peter; Tsien, Joe Z.; Department of Neurology; College of Graduate Studies (2011-07-5)
    The present study investigated the dynamic of the attention focus during observation of different categories of complex scenes and simultaneous consideration of individuals' memory and motivational state. We repeatedly presented four types of complex visual scenes in a pseudo-randomized order and recorded eye movements. Subjects were divided into groups according to their motivational disposition in terms of action orientation and individual rating of scene interest.
  • The Combination of Homocysteine and C-Reactive Protein Predicts the Outcomes of Chinese Patients with Parkinson's Disease and Vascular Parkinsonism

    Zhang, Limin; Yan, Junqiang; Xu, Yunqi; Long, Ling; Zhu, Cansheng; Chen, Xiaohong; Jiang, Ying; Yang, Lijuan; Bian, Lianfang; Wang, Qing; et al. (2011-04-27)
    Background: The elevation of plasma homocysteine (Hcy) and C-reactive protein (CRP) has been correlated to an increased risk of Parkinson's disease (PD) or vascular diseases. The association and clinical relevance of a combined assessment of Hcy and CRP levels in patients with PD and vascular parkinsonism (VP) are unknown.
  • Double Dissociation of Amygdala and Hippocampal Contributions to Trace and Delay Fear Conditioning

    Raybuck, Jonathan D.; Lattal, K. Matthew; Tsien, Joe Z.; Department of Neurology (2011-01-19)
    A key finding in studies of the neurobiology of learning memory is that the amygdala is critically involved in Pavlovian fear conditioning. This is well established in delay-cued and contextual fear conditioning; however, surprisingly little is known of the role of the amygdala in trace conditioning. Trace fear conditioning, in which the CS and US are separated in time by a trace interval, requires the hippocampus and prefrontal cortex. It is possible that recruitment of cortical structures by trace conditioning alters the role of the amygdala compared to delay fear conditioning, where the CS and US overlap. To investigate this, we inactivated the amygdala of male C57BL/6 mice with GABA A agonist muscimol prior to 2-pairing trace or delay fear conditioning. Amygdala inactivation produced deficits in contextual and delay conditioning, but had no effect on trace conditioning. As controls, we demonstrate that dorsal hippocampal inactivation produced deficits in trace and contextual, but not delay fear conditioning. Further, pre- and post-training amygdala inactivation disrupted the contextual but the not cued component of trace conditioning, as did muscimol infusion prior to 1- or 4-pairing trace conditioning. These findings demonstrate that insertion of a temporal gap between the CS and US can generate amygdala-independent fear conditioning. We discuss the implications of this surprising finding for current models of the neural circuitry involved in fear conditioning.
  • Genetic Variation of the Serotonin 2a Receptor Affects Hippocampal Novelty Processing in Humans

    Schott, Bjorn H.; Seidenbecher, Constanze I.; Richter, Sylvia; Wustenberg, Torsten; Debska-Vielhaber, Grazyna; Schubert, Heike; Heinze, Hans-Jochen; Richardson-Klavehn, Alan; Duzel, Emrah; Department of Neurology; et al. (2011-01-18)
    Serotonin (5-hydroxytryptamine, 5-HT) is an important neuromodulator in learning and memory processes. A functional genetic polymorphism of the 5-HT 2a receptor (5-HTR2a His452Tyr), which leads to blunted intracellular signaling, has previously been associated with explicit memory performance in several independent cohorts, but the underlying neural mechanisms are thus far unclear. The human hippocampus plays a critical role in memory, particularly in the detection and encoding of novel information. Here we investigated the relationship of 5-HTR2a His452Tyr and hippocampal novelty processing in 41 young, healthy subjects using functional magnetic resonance imaging (fMRI). Participants performed a novelty/familiarity task with complex scene stimuli, which was followed by a delayed recognition memory test 24 hours later. Compared to His homozygotes, Tyr carriers exhibited a diminished hippocampal response to novel stimuli and a higher tendency to judge novel stimuli as familiar during delayed recognition. Across the cohort, the false alarm rate during delayed recognition correlated negatively with the hippocampal novelty response. Our results suggest that previously reported effects of 5-HTR2a on explicit memory performance may, at least in part, be mediated by alterations of hippocampal novelty processing.
  • The Functional Upregulation of Piriform Cortex Is Associated with Cross-Modal Plasticity in Loss of Whisker Tactile Inputs

    Ye, Bing; Huang, Li; Gao, Zilong; Chen, Ping; Ni, Hong; Guan, Sudong; Zhu, Yan; Wang, Jin-Hui; Mei, Lin; Department of Neurology (2012-08-21)
    Background: Cross-modal plasticity is characterized as the hypersensitivity of remaining modalities after a sensory function is lost in rodents, which ensures their awareness to environmental changes. Cellular and molecular mechanisms underlying cross-modal sensory plasticity remain unclear. We aim to study the role of different types of neurons in cross-modal plasticity.
  • Preoperative Evaluation with fMRI of Patients with Intracranial Gliomas

    Kapsalakis, Ioannis Z.; Kapsalaki, Eftychia Z.; Gotsis, Efstathios D.; Verganelakis, Dimitrios; Toulas, Panagiotis; Hadjigeorgiou, Georgios; Chung, Indug; Fezoulidis, Ioannis; Papadimitriou, Alexandros; Robinson, Joe Sam; et al. (2012--2012)
  • Homologous Recombination Mediates Functional Recovery of Dysferlin Deficiency following AAV5 Gene Transfer

    Grose, William E.; Clark, K. Reed; Griffin, Danielle; Malik, Vinod; Shontz, Kimberly M.; Montgomery, Chrystal L.; Lewis, Sarah; Brown, Robert H.; Janssen, Paul M. L.; Mendell, Jerry R.; et al. (2012-06-15)
    The dysferlinopathies comprise a group of untreatable muscle disorders including limb girdle muscular dystrophy type 2B, Miyoshi myopathy, distal anterior compartment syndrome, and rigid spine syndrome. As with other forms of muscular dystrophy, adeno-associated virus (AAV) gene transfer is a particularly auspicious treatment strategy, however the size of the DYSF cDNA (6.5 kb) negates packaging into traditional AAV serotypes known to express well in muscle (i.e. rAAV1, 2, 6, 8, 9). Potential advantages of a full cDNA versus a mini-gene include: maintaining structural-functional protein domains, evading protein misfolding, and avoiding novel epitopes that could be immunogenic. AAV5 has demonstrated unique plasticity with regards to packaging capacity and recombination of virions containing homologous regions of cDNA inserts has been implicated in the generation of full-length transcripts. Herein we show for the first time in vivo that homologous recombination following AAV5.DYSF gene transfer leads to the production of full length transcript and protein. Moreover, gene transfer of full-length dysferlin protein in dysferlin deficient mice resulted in expression levels sufficient to correct functional deficits in the diaphragm and importantly in skeletal muscle membrane repair. Intravascular regional gene transfer through the femoral artery produced high levels of transduction and enabled targeting of specific muscle groups affected by the dysferlinopathies setting the stage for potential translation to clinical trials. We provide proof of principle that AAV5 mediated delivery of dysferlin is a highly promising strategy for treatment of dysferlinopathies and has far-reaching implications for the therapeutic delivery of other large genes.
  • Dihydrotestosterone Ameliorates Degeneration in Muscle, Axons and Motoneurons and Improves Motor Function in Amyotrophic Lateral Sclerosis Model Mice

    Yoo, Young-Eun; Ko, Chien-Ping; Mei, Lin; Department of Neurology (2012-05-14)
    Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by a progressive loss of motoneurons. The clinical symptoms include skeletal muscle weakness and atrophy, which impairs motor performance and eventually leads to respiratory failure. We tested whether dihydrotestosterone (DHT), which has both anabolic effects on muscle and neuroprotective effects on axons and motoneurons, can ameliorate clinical symptoms in ALS. A silastic tube containing DHT crystals was implanted subcutaneously in SOD1-G93A mice at early symptomatic age when decreases in body weight and grip-strength were observed as compared to wild-type mice. DHT-treated SOD1-G93A mice demonstrated ameliorated muscle atrophy and increased body weight, which was associated with stronger grip-strength. DHT treatment increased the expression of insulin-like growth factor-1 in muscle, which can exert myotrophic as well as neurotrophic effects through retrograde transport. DHT treatment attenuated neuromuscular junction denervation, and axonal and motoneuron loss. DHT-treated SOD1-G93A mice demonstrated improvement in motor behavior as assessed by rota-rod and gait analyses, and an increased lifespan. Application of DHT is a relatively simple and non-invasive procedure, which may be translated into therapy to improve the quality of life for ALS patients.

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