Vikram G Shakkottai

University of Michigan, Ann Arbor, Michigan, United States

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Publications (30)190.61 Total impact

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    ABSTRACT: Neuronal atrophy in neurodegenerative diseases is commonly viewed as an early event in a continuum that ultimately results in neuronal loss. In a mouse model of the polyglutamine disorder spinocerebellar ataxia type 1 (SCA1), we tested the hypothesis that cerebellar Purkinje neuron atrophy serves an adaptive role rather than being simply a nonspecific response to injury. In acute cerebellar slices from SCA1 mice, we find that Purkinje neuron pacemaker firing is initially normal but, with the onset of motor dysfunction, becomes disrupted, accompanied by abnormal depolarization. Remarkably, subsequent Purkinje cell atrophy is associated with a restoration of pacemaker firing. The early inability of Purkinje neurons to support repetitive spiking is due to unopposed calcium currents resulting from a reduction in large-conductance calcium-activated potassium (BK) and subthreshold-activated potassium channels. The subsequent restoration of SCA1 Purkinje neuron firing correlates with the recovery of the density of these potassium channels that accompanies cell atrophy. Supporting a critical role for BK channels, viral-mediated increases in BK channel expression in SCA1 Purkinje neurons improves motor dysfunction and partially restores Purkinje neuron morphology. Cerebellar perfusion of flufenamic acid, an agent that restores the depolarized membrane potential of SCA1 Purkinje neurons by activating potassium channels, prevents Purkinje neuron dendritic atrophy. These results suggest that Purkinje neuron dendritic remodeling in ataxia is an adaptive response to increases in intrinsic membrane excitability. Similar adaptive remodeling could apply to other vulnerable neuronal populations in neurodegenerative disease. In neurodegenerative disease, neuronal atrophy has long been assumed to be an early nonspecific event preceding neuronal loss. However, in a mouse model of spinocerebellar ataxia type 1 (SCA1), we identify a previously unappreciated compensatory role for neuronal shrinkage. Purkinje neuron firing in these mice is initially normal, but is followed by abnormal membrane depolarization resulting from a reduction in potassium channels. Subsequently, these electrophysiological effects are counteracted by cell atrophy, which by restoring normal potassium channel membrane density, re-establishes pacemaker firing. Reversing the initial membrane depolarization improved motor function and Purkinje neuron morphology in the SCA1 mice. These results suggest that Purkinje neuron remodeling in ataxia is an active compensatory response that serves to normalize intrinsic membrane excitability. Copyright © 2015 the authors 0270-6474/15/3511293-16$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2015; 35(32):11292-307. DOI:10.1523/JNEUROSCI.1357-15.2015 · 6.75 Impact Factor
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    ABSTRACT: The contributions of vascular risk factors to spinocerebellar ataxia (SCA) are not known. We studied 319 participants with SCA 1, 2, 3, and 6 and repeatedly measured clinical severity using the Scale for Assessment and Rating of Ataxia (SARA) for 2 years. Vascular risk factors were summarized by CHA2DS2-VASc scores as the vascular risk factor index. We employed regression models to study the effects of vascular risk factors on ataxia onset and progression after adjusting for age, sex, and pathological CAG repeats. Our secondary analyses took hyperlipidemia into account. Nearly 60% of SCA participants were at low vascular risks with CHA2DS2-VASc = 0, and 31% scored 2 or greater. Higher CHA2DS2-VASc scores were not associated with either earlier onset or faster progression of ataxia. These findings were not altered after accounting for hyperlipidemia. Vascular risks are not common in SCAs and are not associated with earlier onset or faster ataxia progression.
    02/2015; 5:287. DOI:10.7916/D89885S0
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    ABSTRACT: The aim of this study was to investigate the association between drug exposure and disease severity in SCA types 1, 2, 3 and 6. The Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) enrolled 319 participants with SCA1, 2, 3, and 6 from 12 medical centers in the United States and repeatedly measured clinical severity by the Scale for Assessment and Rating of Ataxia (SARA), the Unified Huntington's Disease Rating Scale part IV (UHDRS-IV), and the 9-item Patient Health Questionnaire during July 2009 to May 2012. We employed generalized estimating equations in regression models to study the longitudinal effects of coenzyme Q10 (CoQ10), statin, and vitamin E on clinical severity of ataxia after adjusting for age, sex, and pathological CAG repeat number. Cross-sectionally, exposure to CoQ10 was associated with lower SARA and higher UHDRS-IV scores in SCA1 and 3. No association was found between statins, vitamin E, and clinical outcome. Longitudinally, CoQ10, statins, and vitamin E did not change the rates of clinical deterioration indexed by SARA and UHDRS-IV scores within 2 years. CoQ10 is associated with better clinical outcome in SCA1 and 3. These drug exposures did not appear to influence clinical progression within 2 years. Further studies are warranted to confirm the association. © 2014 International Parkinson and Movement Disorder Society
    Movement Disorders 11/2014; 30(2). DOI:10.1002/mds.26088 · 5.68 Impact Factor
  • James Dell'Orco · Aaron Wasserman · Ravi Chopra · Vikram Shakkottai
    43rd Annual Meeting of the Child-Neurology-Society; 10/2014
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    ABSTRACT: Background: Ocular motor abnormalities reflect the varied neuropathology of spinocerebellar ataxias (SCAs) and may serve to clinically distinguish the different SCAs. We analyzed the various eye movement abnormalities detected prospectively at the baseline visit during a large multicenter natural history study of SCAs 1, 2, 3, and 6. Methods: The data were prospectively collected from 12 centers in the United States in patients with SCAs 1, 2, 3, and 6, as part of the Clinical Research Consortium for Spinocerebellar Ataxias (NIH-CRC-SCA). Patient characteristics, ataxia rating scales, the Unified Huntington Disease Rating Scale functional examination, and clinical staging were used. Eye movement abnormalities including nystagmus, disorders of saccades and pursuit, and ophthalmoparesis were recorded, and factors influencing their occurrence were examined. Results: A total of 301 patients participated in this study, including 52 patients with SCA 1, 64 with SCA 2, 117 with SCA 3, and 68 with SCA 6. Although no specific ocular motor abnormality was pathognomonic to any SCA, significant differences were noted in their occurrence among different disorders. SCA 6 was characterized by frequent occurrence of nystagmus and abnormal pursuit and rarity of slow saccades and ophthalmoparesis and SCA 2 by the frequent occurrence of slow saccades and infrequent nystagmus and dysmetric saccades. SCA 1 and SCA 3 subjects had a more even distribution of eye movement abnormalities. Conclusions: Prospective data from a large cohort of patients with SCAs 1, 2, 3, and 6 provide statistical validation that the SCAs exhibit distinct eye movement abnormalities that are useful in identifying the genotypes. Many of the abnormalities correlate with greater disease severity measures.
    Journal of neuro-ophthalmology: the official journal of the North American Neuro-Ophthalmology Society 09/2014; 35(1). DOI:10.1097/WNO.0000000000000167 · 1.81 Impact Factor
  • Ravi Chopra · Vikram G Shakkottai
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    ABSTRACT: Polyglutamine diseases are a class of neurodegenerative diseases that share an expansion of a glutamine-encoding CAG tract in the respective disease genes as a central hallmark. In all of these diseases there is progressive degeneration in a select subset of neurons, and the mechanisms behind this degeneration remain unclear. Emerging evidence from animal models of disease has identified abnormalities in synaptic signaling and intrinsic excitability in affected neurons, which coincide with the onset of symptoms and precede apparent neuropathology. The appearance of these early changes suggests that altered neuronal activity might be an important component of network dysfunction and that these alterations in network physiology could contribute to symptoms of disease. Here we review abnormalities in neuronal function that have been identified in both animal models and patients, and highlight ways in which these changes in neuronal activity may contribute to disease symptoms. We then review the literature supporting an emerging role for abnormalities in neuronal activity as a driver of neurodegeneration. Finally, we identify common themes that emerge from studies of neuronal dysfunction in polyglutamine disease.
    Journal of the American Society for Experimental NeuroTherapeutics 07/2014; 11(4). DOI:10.1007/s13311-014-0289-7 · 3.88 Impact Factor
  • Vikram G Shakkottai
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    ABSTRACT: Dystonia is a neurologic disorder characterized by sustained involuntary muscle contractions. Lesions responsible for unilateral secondary dystonia are confined to the putamen, caudate, globus pallidus, and thalamus. Dysfunction of these structures is suspected to play a role in both primary and secondary dystonia. Recent evidence has suggested that the cerebellum may play a role in the pathophysiology of dystonia. The role of the cerebellum in ataxia, a disorder of motor incoordination is well established. How may the cerebellum contribute to two apparently very different movement disorders? This review will discuss the idea of whether in some cases, ataxia and dystonia lie in the same clinical spectrum and whether graded perturbations in cerebellar function may explain a similar causative role for the cerebellum in these two different motor disorders. The review also proposes a model for cerebellar dystonia based on the available animal models of this disorder.
    The Cerebellum 05/2014; 13(5). DOI:10.1007/s12311-014-0572-5 · 2.86 Impact Factor
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    ABSTRACT: Recent evidence suggests that dystonia, a movement disorder characterized by sustained involuntary muscle contractions, can be associated with cerebellar abnormalities. The basis for how functional changes in the cerebellum can cause dystonia is poorly understood. Here we identify alterations in physiology in Atcay(ji-hes) mice which in addition to ataxia, have an abnormal gait with hind limb extension and toe walking, reminiscent of human dystonic gait. No morphological abnormalities in the brain accompany the dystonia, but partial cerebellectomy causes resolution of the stiff-legged gait, suggesting that cerebellar dysfunction contributes to the dystonic gait of Atcay(ji-hes) mice. Recordings from Purkinje and deep cerebellar nuclear (DCN) neurons in acute brain slices were used to determine the physiological correlates of dystonia in the Atcay(ji-hes) mice. Approximately 50% of cerebellar Purkinje neurons fail to display the normal repetitive firing characteristic of these cells. In addition, DCN neurons exhibit increased intrinsic firing frequencies with a subset of neurons displaying bursts of action potentials. This increased intrinsic excitability of DCN neurons is accompanied by a reduction in after-hyperpolarization currents mediated by small-conductance calcium-activated potassium (SK) channels. An activator of SK channels reduces DCN neuron firing frequency in acute cerebellar slices and improves the dystonic gait of Atcay(ji-hes) mice. These results suggest that a combination of reduced Purkinje neuron activity and increased DCN intrinsic excitability can result in a combination of ataxia and a dystonia-like gait in mice.
    Neurobiology of Disease 04/2014; 67. DOI:10.1016/j.nbd.2014.03.020 · 5.20 Impact Factor
  • Ravi Chopra · Vikram G Shakkottai
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    ABSTRACT: The cerebellum is an important structure for accurate control and timing of movement, and Purkinje neurons in the cerebellar cortex are key players in cerebellar motor control. Cerebellar dysfunction can result in ataxia, a disorder characterized by postural instability, gait disturbances and motor incoordination. Cerebellar ataxia is a symptom of a number of conditions, and the emerging evidence that Purkinje neuron dysfunction, in particular, abnormal Purkinje neuron repetitive firing, is a major driver of motor dysfunction in a subset of dominantly inherited ataxias is dicussed. Abnormalities in Purkinje neuron excitability that are observed in mouse models of each of these disorders, and where appropriate describe studies linking particular ion channels to aberrant excitability are also discussed. Common mechanisms of dysfunction and speculate about potential therapeutic targets, suggesting that Purkinje neuron firing abnormalities are a novel target for improving motor dysfunction in patients with some forms of dominantly inherited ataxia are proposed.
    Future Neurology 03/2014; 9(2):187-196. DOI:10.2217/fnl.14.6
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    ABSTRACT: Recent evidence suggests that dystonia, a movement disorder characterized by sustained involuntary muscle contractions, can be associated with cerebellar abnormalities. The basis for how functional changes in the cerebellum can cause dystonia is poorly understood. Here we identify alterations in physiology in Atcayji-hes mice which in addition to ataxia, have an abnormal gait with hind limb extension and toe walking, reminiscent of human dystonic gait. No morphological abnormalities in the brain accompany the dystonia, but partial cerebellectomy causes resolution of the stiff-legged gait, suggesting that cerebellar dysfunction contributes to the dystonic gait of Atcayji-hes mice. Recordings from Purkinje and deep cerebellar nuclear (DCN) neurons in acute brain slices were used to determine the physiological correlates of dystonia in the Atcayji-hes mice. Approximately 50% of cerebellar Purkinje neurons fail to display the normal repetitive firing characteristic of these cells. In addition, DCN neurons exhibit increased intrinsic firing frequencies with a subset of neurons displaying bursts of action potentials. This increased intrinsic excitability of DCN neurons is accompanied by a reduction in after-hyperpolarization currents mediated by small-conductance calcium-activated potassium (SK) channels. An activator of SK channels reduces DCN neuron firing frequency in acute cerebellar slices and improves the dystonic gait of Atcayji-hes mice. These results suggest that a combination of reduced Purkinje neuron activity and increased DCN intrinsic excitability can result in a combination of ataxia and a dystonia-like gait in mice.
    Neurobiology of Disease 01/2014; · 5.20 Impact Factor
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    ABSTRACT: All spinocerebellar ataxias (SCAs) are rare diseases. SCA1, 2, 3 and 6 are the four most common SCAs, all caused by expanded polyglutamine-coding CAG repeats. Their pathomechanisms are becoming increasingly clear and well-designed clinical trials will be needed. To characterize the clinical manifestations of spinocerebellar ataxia (SCA) 1, 2, 3 and 6 and their natural histories in the United States (US), we conducted a prospective multicenter study utilized a protocol identical to the European consortium study, using the Scale for the Assessment and Rating of Ataxia (SARA) score as the primary outcome, with follow-ups every 6 months up to 2 years. We enrolled 345 patients (60 SCA1, 75 SCA2, 138 SCA3 and 72 SCA6) at 12 US centers. SCA6 patients had a significantly later onset, and SCA2 patients showed greater upper-body ataxia than patients with the remaining SCAs. The annual increase of SARA score was greater in SCA1 patients (mean +/- SE: 1.61 +/- 0.41) than in SCA2 (0.71 +/- 0.31), SCA3 (0.65 +/- 0.24) and SCA6 (0.87 +/- 0.28) patients (p = 0.049). The functional stage also worsened faster in SCA1 than in SCA2, 3 and 6 (p = 0.002). The proportions of different SCA patients in US differ from those in the European consortium study, but as in the European patients, SCA1 progress faster than those with SCA2, 3 and 6. Later onset in SCA6 and greater upper body ataxia in SCA2 were noted. We conclude that progression rates of these SCAs were comparable between US and Europe cohorts, suggesting the feasibility of international collaborative clinical studies.
    Orphanet Journal of Rare Diseases 11/2013; 8(1):177. DOI:10.1186/1750-1172-8-177 · 3.96 Impact Factor
  • Vikram G Shakkottai · Brent L Fogel
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    ABSTRACT: The autosomal dominant spinocerebellar ataxias are a diverse and clinically heterogeneous group of disorders characterized by degeneration and dysfunction of the cerebellum and its associated pathways. Clinical and diagnostic evaluation can be challenging because of phenotypic overlap among causes, and a stratified and systematic approach is essential. Recent advances include the identification of additional genes causing dominant genetic ataxia, a better understanding of cellular pathogenesis in several disorders, the generation of new disease models that may stimulate development of new therapies, and the use of new DNA sequencing technologies, including whole-exome sequencing, to improve diagnosis.
    Neurologic Clinics 11/2013; 31(4):987-1007. DOI:10.1016/j.ncl.2013.04.006 · 1.61 Impact Factor
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    ABSTRACT: Machado-Joseph disease (MJD) is a dominantly inherited ataxia caused by a polyglutamine-coding expansion in the ATXN3 gene. Suppressing expression of the toxic gene product represents a promising approach to therapy for MJD and other polyglutamine diseases. We performed an extended therapeutic trial of RNA interference (RNAi) targeting ATXN3 in a mouse model expressing the full human disease gene and recapitulating key disease features. Adeno-associated virus encoding a microRNA-like molecule, miRATXN3, was delivered bilaterally into the cerebellum of 6-8 week old MJD mice, which were then followed to end-stage disease to assess the safety and efficacy of anti-ATXN3 RNAi. Despite effective, lifelong suppression of ATXN3 in the cerebellum and the apparent safety of miRATXN3, motor impairment was not ameliorated in treated MJD mice and survival was not prolonged. These results with an otherwise effective RNAi agent suggest that targeting a large extent of the cerebellum alone may not be sufficient for effective human therapy. Artificial miRNAs or other nucleotide-based suppression strategies targeting ATXN3 more widely in the brain should be considered in future preclinical tests.Molecular Therapy (2013); doi:10.1038/mt.2013.144.
    Molecular Therapy 06/2013; 21(10). DOI:10.1038/mt.2013.144 · 6.43 Impact Factor
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    ABSTRACT: To identify the causative gene in spinocerebellar ataxia (SCA) 22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21-q23. We previously characterized a large Chinese family with progressive ataxia designated SCA22, which overlaps with the locus of SCA19. The disease locus in a French family and an Ashkenazi Jewish American family was also mapped to this region. Members from all 3 families were enrolled. Whole exome sequencing was performed to identify candidate mutations, which were narrowed by linkage analysis and confirmed by Sanger sequencing and cosegregation analyses. Mutational analyses were also performed in 105 Chinese and 55 Japanese families with cerebellar ataxia. Mutant gene products were examined in a heterologous expression system to address the changes in protein localization and electrophysiological functions. We identified heterozygous mutations in the voltage-gated potassium channel Kv4.3-encoding gene KCND3: an in-frame 3-nucleotide deletion c.679_681delTTC p.F227del in both the Chinese and French pedigrees, and a missense mutation c.1034G>T p.G345V in the Ashkenazi Jewish family. Direct sequencing of KCND3 further identified 3 mutations, c.1034G>T p.G345V, c.1013T>C p.V338E, and c.1130C>T p.T377M, in 3 Japanese kindreds. Immunofluorescence analyses revealed that the mutant p.F227del Kv4.3 subunits were retained in the cytoplasm, consistent with the lack of A-type K(+) channel conductance in whole cell patch-clamp recordings. Our data identify the cause of SCA19/22 in patients of diverse ethnic origins as mutations in KCND3. These findings further emphasize the important role of ion channels as key regulators of neuronal excitability in the pathogenesis of cerebellar degeneration. ANN NEUROL 2012;72:859-869.
    Annals of Neurology 12/2012; 72(6):859-69. DOI:10.1002/ana.23701 · 11.91 Impact Factor
  • Neurology 04/2012; 78(Meeting Abstracts 1):S12.002-S12.002. DOI:10.1212/WNL.78.1_MeetingAbstracts.S12.002 · 8.30 Impact Factor
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    ABSTRACT: Objective:To identify the causative gene in spinocerebellar ataxia (SCA) 22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21‐q23. Methods:We previously characterized a large Chinese family with progressive ataxia designated SCA22, which overlaps with the locus of SCA19. The disease locus in a French family and an Ashkenazi Jewish American family was also mapped to this region. Members from all 3 families were enrolled. Whole exome sequencing was performed to identify candidate mutations, which were narrowed by linkage analysis and confirmed by Sanger sequencing and cosegregation analyses. Mutational analyses were also performed in 105 Chinese and 55 Japanese families with cerebellar ataxia. Mutant gene products were examined in a heterologous expression system to address the changes in protein localization and electrophysiological functions. Results:We identified heterozygous mutations in the voltage‐gated potassium channel Kv4.3‐encoding gene KCND3: an in‐frame 3‐nucleotide deletion c.679_681delTTC p.F227del in both the Chinese and French pedigrees, and a missense mutation c.1034G>T p.G345V in the Ashkenazi Jewish family. Direct sequencing of KCND3 further identified 3 mutations, c.1034G>T p.G345V, c.1013T>C p.V338E, and c.1130C>T p.T377M, in 3 Japanese kindreds. Immunofluorescence analyses revealed that the mutant p.F227del Kv4.3 subunits were retained in the cytoplasm, consistent with the lack of A‐type K+ channel conductance in whole cell patch‐clamp recordings. Interpretation:Our data identify the cause of SCA19/22 in patients of diverse ethnic origins as mutations in KCND3. These findings further emphasize the important role of ion channels as key regulators of neuronal excitability in the pathogenesis of cerebellar degeneration. ANN NEUROL 2012;72:859–869.
    Annals of Neurology 01/2012; 72(6). · 11.91 Impact Factor
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    ABSTRACT: The relationship between cerebellar dysfunction, motor symptoms, and neuronal loss in the inherited ataxias, including the polyglutamine disease spinocerebellar ataxia type 3 (SCA3), remains poorly understood. We demonstrate that before neurodegeneration, Purkinje neurons in a mouse model of SCA3 exhibit increased intrinsic excitability resulting in depolarization block and the loss of the ability to sustain spontaneous repetitive firing. These alterations in intrinsic firing are associated with increased inactivation of voltage-activated potassium currents. Administration of an activator of calcium-activated potassium channels, SKA-31, partially corrects abnormal Purkinje cell firing and improves motor function in SCA3 mice. Finally, expression of the disease protein, ataxin-3, in transfected cells increases the inactivation of Kv3.1 channels and shifts the activation of Kv1.2 channels to more depolarized potentials. Our results suggest that in SCA3, early Purkinje neuron dysfunction is associated with altered physiology of voltage-activated potassium channels. We further suggest that the observed changes in Purkinje neuron physiology contribute to disease pathogenesis, underlie at least some motor symptoms, and represent a promising therapeutic target in SCA3.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/2011; 31(36):13002-14. DOI:10.1523/JNEUROSCI.2789-11.2011 · 6.75 Impact Factor
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    Ting Yu · Vikram G Shakkottai · Chan Chung · Andrew P Lieberman
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    ABSTRACT: Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disorder caused by mutations in the NPC1 or NPC2 genes. Loss of function mutations in either gene disrupt intracellular lipid trafficking and lead to a clinically heterogeneous phenotype that invariably includes neurological dysfunction and early death. The mechanism by which impaired lipid transport leads to neurodegeneration is poorly understood. Here we used mice with a conditional null allele to establish the timing and cell type that underlie neurodegeneration due to Npc1 deficiency. We show that global deletion of Npc1 in adult mice leads to progressive weight loss, impaired motor function and early death in a time course similar to that resulting from germline deletion. These phenotypes are associated with the occurrence of characteristic neuropathology including patterned Purkinje cell loss, axonal spheroids and reactive gliosis, demonstrating that there is not a significant developmental component to NPC neurodegeneration. Furthermore, we show that these same changes occur when Npc1 is specifically deleted only in neurons, establishing that neuronal deficiency is sufficient to mediate central nervous system (CNS) disease. In contrast, astrocyte-specific deletion does not impact behavioral phenotypes, CNS histopathology or synaptic function. We conclude that defects arising in neurons, but not in astrocytes, are the determining factor in the development of NPC neuropathology.
    Human Molecular Genetics 08/2011; 20(22):4440-51. DOI:10.1093/hmg/ddr372 · 6.68 Impact Factor
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    ABSTRACT: Pathways regulating neuronal vulnerability are poorly understood, yet are central to identifying therapeutic targets for degenerative neurological diseases. Here, we characterize mechanisms underlying neurodegeneration in Niemann-Pick type C (NPC) disease, a lysosomal storage disorder characterized by impaired cholesterol trafficking. To date, the relative contributions of neuronal and glial defects to neuron loss are poorly defined. Using gene targeting, we generate Npc1 conditional null mutant mice. Deletion of Npc1 in mature cerebellar Purkinje cells leads to an age-dependent impairment in motor tasks, including rotarod and balance beam performance. Surprisingly, these mice did not show the early death or weight loss that are characteristic of global Npc1 null mice, suggesting that Purkinje cell degeneration does not underlie these phenotypes. Histological examination revealed the progressive loss of Purkinje cells in an anterior-to-posterior gradient. This cell autonomous neurodegeneration occurs in a spatiotemporal pattern similar to that of global knockout mice. A subpopulation of Purkinje cells in the posterior cerebellum exhibits marked resistance to cell death despite Npc1 deletion. To explore this selective response, we investigated the electrophysiological properties of vulnerable and susceptible Purkinje cell subpopulations. Unexpectedly, Purkinje cells in both subpopulations displayed no electrophysiological abnormalities prior to degeneration. Our data establish that Npc1 deficiency leads to cell autonomous, selective neurodegeneration and suggest that the ataxic symptoms of NPC disease arise from Purkinje cell death rather than cellular dysfunction. © The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected] /* */
    Human Molecular Genetics 12/2009; 19(5):837-47. DOI:10.1093/hmg/ddp552 · 6.68 Impact Factor
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    Vikram G Shakkottai · Henry L Paulson
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    ABSTRACT: The ataxias constitute a heterogeneous group of diseases in which cerebellar dysfunction typically underlies the major neurologic manifestations. It is increasingly clear that ataxia can result directly from mutations in ion channels or from perturbations in ion channel physiology in the absence of a primary channel defect. Neuronal dysfunction stemming from perturbed channel activity likely explains some motor deficits in episodic and degenerative ataxias. Understanding these pathophysiologic changes may reveal novel therapeutic targets for symptomatic treatment of ataxia.
    Archives of neurology 10/2009; 66(10):1196-201. DOI:10.1001/archneurol.2009.212 · 7.01 Impact Factor

Publication Stats

631 Citations
190.61 Total Impact Points

Institutions

  • 2009–2015
    • University of Michigan
      • Department of Neurology
      Ann Arbor, Michigan, United States
  • 2011
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2008
    • Washington University in St. Louis
      • Department of Neurology
      San Luis, Missouri, United States
  • 2001–2004
    • University of California, Irvine
      • Department of Physiology & Biophysics
      Irvine, California, United States