Progress in Neurobiology (PROG NEUROBIOL)

Publications in this journal

• Article: Scientific and Ethical Issues Related to Stem Cell Research and Interventions in Neurodegenerative Disorders of the Brain.

  Roger A Barker, Inez De Beaufort
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  ABSTRACT: Should patients with Parkinson's disease participate in research involving stem cell treatments? Are induced pluripotent stem cells (iPSC) the ethical solution to the moral issues regarding embryonic stem cells? How can we adapt trial designs to best assess small numbers of patients in receipt of invasive experimental therapies? Over the last 20 years there has been a revolution in our ability to make stem cells from different sources and use them for therapeutic gain in disorders of the brain. These cells, which are defined by their capacity to proliferate indefinitely as well as differentiate into selective phenotypic cell types, are viewed as being an especially attractive for studying disease processes and for grafting in patients with chronic incurable neurodegenerative disorders of the CNS such as Parkinson's Disease (PD). In this review we briefly discuss and summarise where our understanding of stem cell biology has taken us relative to the clinic and patients, before dealing with some of the major ethical issues that work of this nature generates. This includes issues to do with the source of the cells, their ownership and exploitation along with questions about patient recruitment, consent and trial design when they translate to the clinic for therapeutic use.
  Progress in Neurobiology 05/2013;
• Article: Early application of deep brain stimulation: Clinical and ethical aspects.

  Christiane Woopen, K Amande M Pauls, Anne Koy, Elena Moro, Lars Timmermann
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  ABSTRACT: Deep brain stimulation (DBS) has proven to be a successful therapeutic approach in several patients with movement disorders such as Parkinsońs disease and dystonia. Hitherto its application was mainly restricted to advanced disease patients resistant to medication or with severe treatment side effects. However, there is now growing interest in earlier application of DBS, aimed at improving clinical outcomes, quality of life, and avoiding psychosocial consequences of chronic disease-related impairments. We address the clinical and ethical aspects of two "early" uses of DBS, 1) DBS early in the course of the disease, and 2) DBS early in life (i.e. in children). Possible benefits, risks and burdens are discussed and thoroughly considered. Further research is needed to obtain a careful balance between exposing vulnerable patients to potential severe surgical risks and excluding them from a potentially good outcome.
  Progress in Neurobiology 04/2013;
• Article: Diagnosis and Management of Alzheimer's Disease: Past, Present and Future Ethical Issues.

  S Gauthier, A Leuzy, E Racine, P Rosa-Neto
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  ABSTRACT: There is great interest in the ethical issues associated with Alzheimer's disease (AD) and related dementias given the prevalence of AD and the evolving neuroscience landscape in matters of diagnoses and therapeutics. Much of the ethics discussion arises in the tension between the principle of not doing harm (principle of non-maleficence) in this vulnerable population and the development of effective treatments (principle of beneficence). Autonomy and capacity issues are also numerous, wide-ranging, and concern (1) day to day affairs such as driving safely and spending money wisely, (2) life-time events such as designating a legal representative in case of incapacity, making a will, (3) consenting to treatment and diagnostic procedures, (4) participating in research. The latter issue is particularly thorny and illustrates well the complexity of tackling concerns related to capacity. The impetus to protect AD patients has partly led to ethics regulation and policies making research on inapt patients more difficult because of stringent requirements for signed informed consent or for showing the value of the research to this specific patient population. New issues are arising that relate to earlier diagnosis using biomarkers and (possibly soon) the use of drugs that modify disease progression. We here summarize and discuss the different ethical issues associated with AD from a historical perspective, with emphasis on diagnostic and treatments issues.
  Progress in Neurobiology 04/2013;
• Article: Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage: A challenge for neuroprotection.

  Julien Puyal, Vanessa Ginet, Peter G H Clarke
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  ABSTRACT: There is currently no approved neuroprotective pharmacotherapy for acute conditions such as stroke and cerebral asphyxia. One of the reasons for this may be the multiplicity of cell death mechanisms, because inhibition of a particular mechanism leaves the brain vulnerable to alternative ones. It is therefore essential to understand the different cell death mechanisms and their interactions. We here review the multiple signaling pathways underlying each of the three main morphological types of cell death - apoptosis, autophagic cell death, and necrosis - emphasizing their importance in the neuronal death that occurs during cerebral ischemia and hypoxia-ischemia, and we analyze the interactions between the different mechanisms. Finally, we discuss the implications of the multiplicity of cell death mechanisms for the design of neuroprotective strategies.
  Progress in Neurobiology 04/2013;
• Article: Matrix metalloproteinase-2 and -9 as promising benefactors in development, plasticity and repair of the nervous system.

  Mieke Verslegers, Kim Lemmens, Inge Van Hove, Lieve Moons
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  ABSTRACT: It has been 50 years since Gross and Lapiere discovered collagenolytic activity during tadpole tail metamorphosis, which was later on revealed as MMP-1, the founding member of the matrix metalloproteinases (MMPs). Currently, MMPs constitute a large group of endoproteases that are not only able to cleave all protein components of the extracellular matrix, but also to activate or inactivate many other signaling molecules, such as receptors, adhesion molecules and growth factors. Elevated MMP levels are associated with an increasing number of injuries and disorders, such as cancer, inflammation and auto-immune diseases. Yet, MMP upregulation has also been implicated in many physiological functions such as embryonic development, wound healing and angiogenesis and therefore, these proteinases are considered to be crucial mediators in many biological processes. Over the past decennia, MMP research has gained considerable attention in several pathologies, most prominently in the field of cancer metastasis, and more recent investigations also focus on the nervous system, with a striking emphasis on the gelatinases, MMP-2 and MMP-9. Unfortunately, the contribution of these gelatinases to neuropathological disorders, like multiple sclerosis and Alzheimer's disease, has overshadowed their potential as modulators of fundamental nervous system functions. Within this review, we wish to highlight the currently known or suggested actions of MMP-2 and MMP-9 in the developing and adult nervous system and their potential to improve repair or regeneration after nervous system injury.
  Progress in Neurobiology 04/2013;
• Article: Conversion of sensory signals into perceptions, memories and decisions.

  Ranulfo Romo
  Progress in Neurobiology 04/2013; 103:1-2.
• Article: Tau Degradation: The Ubiquitin-Proteasome System versus the Autophagy-Lysosome System.

  Min Jae Lee, Jung Hoon Lee, David C Rubinsztein
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  ABSTRACT: The ubiquitin-proteasome system (UPS) and the autophagy-lysosome system are two major protein quality control mechanisms in eukaryotic cells. While the UPS has been considered for decades as the critical regulator in the degradation of various aggregate-prone proteins, autophagy has more recently been shown to be an important pathway implicated in neuronal health and disease. The two hallmark lesions of Alzheimer's disease (AD) are extracellular β-amyloid plaques and intracellular tau tangles. It has been suggested that tau accumulation is pathologically more relevant to the development of neurodegeneration and cognitive decline in AD patients than β-amyloid plaques. Here, we review the UPS and autophagy-mediated tau clearance mechanisms and outline the biochemical connections between these two processes. In addition, we discuss pharmacological methods that target these degradation systems for the treatment and prevention of AD.
  Progress in Neurobiology 03/2013;
• Article: Reconsider Alzheimer's disease by the 'calpain-cathepsin hypothesis'-A perspective review.

  Tetsumori Yamashima
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  ABSTRACT: Alzheimer's disease (AD) is characterized by slowly progressive neuronal death, but its molecular cascade remains elusive for over 100 years. Since accumulation of autophagic vacuoles (also called granulo-vacuolar degenerations) represents one of the pathologic hallmarks of degenerating neurons in AD, a causative connection between autophagy failure and neuronal death should be present. The aim of this perspective review is at considering such underlying mechanism of AD that age-dependent oxidative stresses may affect the autophagic-lysosomal system via carbonylation and cleavage of heat-shock protein 70.1 (Hsp70.1). AD brains exhibit gradual but continual ischemic insults that cause perturbed Ca(2+) homeostasis, calpain activation, amyloid ß deposition, and oxidative stresses. Membrane lipids such as linoleic and arachidonic acids are vulnerable to the cumulative oxidative stresses, generating a toxic peroxidation product 'hydroxynonenal' that can carbonylate Hsp70.1. Recent data advocate for dual roles of Hsp70.1 as a molecular chaperone for damaged proteins and a guardian of lysosomal integrity. Accordingly, impairments of lysosomal autophagy and stabilization may be driven by the calpain-mediated cleavage of carbonylated Hsp70.1, and this causes lysosomal permeabilization and/or rupture with the resultant release of the cell degradation enzyme, cathepsins (calpain-cathepsin hypothesis). Here, the author discusses three topics; (1) how age-related decrease in lysosomal and autophagic activities has a causal connection to programmed neuronal necrosis in sporadic AD, (2) how genetic factors such as apolipoprotein E and presenilin 1 can facilitate lysosomal destabilization in the sequential molecular events, and (3) whether a single cascade can simultaneously account for implications of all players previously reported. In conclusion, Alzheimer neuronal death conceivably occurs by the similar 'calpain-hydroxynonenal-Hsp70.1-cathepsin cascade' with ischemic neuronal death. Blockade of calpain and/or extra-lysosomal cathepsins as well as scavenging of hydroxynonenal would become effective AD therapeutic approaches.
  Progress in Neurobiology 03/2013;
• Article: Pain and Analgesia: The Value of Salience Circuits.

  David Borsook, Robert Edwards, Igor Elman, Lino Becerra, Jon Levine
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  ABSTRACT: Evaluating external and internal stimuli is critical to survival. Potentially tissue-damaging conditions generate sensory experiences that the organism must respond to in an appropriate, adaptive manner (e.g., withdrawal from the noxious stimulus, if possible, or seeking relief from pain and discomfort). The importance we assign to a signal generated by a noxious state, its salience, reflects our belief as to how likely the underlying situation is to impact our chance of survival. Importantly, it has been hypothesized that aberrant functioning of the brain circuits which assign salience values to stimuli may contribute to chronic pain. We describe examples of this phenomenon, including 'feeling pain' in the absence of a painful stimulus, reporting minimal pain in the setting of major trauma, having an 'analgesic' response in the absence of an active treatment, or reporting no pain relief after administration of a potent analgesic medication, which may provide critical insights into the role that salience circuits play in contributing to numerous conditions characterized by persistent pain. Collectively, a refined understanding of abnormal activity or connectivity of elements within the salience network may allow us to more effectively target interventions to relevant components of this network in patients with chronic pain.
  Progress in Neurobiology 03/2013;
• Article: Current status of chemokines in the adult CNS.

  Annabelle Réaux-Le Goazigo, Juliette Van Steenwinckel, William Rostène, Stéphane Mélik Parsadaniantz
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  ABSTRACT: Chemokines - chemotactic cytokines - are small secreted proteins that attract and activate immune and non-immune cells in vitro and in vivo. It has been suggested that chemokines and their receptors play a role in the central nervous system (CNS), in addition to their well established role in the immune system. We focus here on three chemokines - CXCL12 (C-X-C motif ligand 12), CCL2 (C-C motif ligand 2), and CX3CL1 (C-X-3C motif ligand 1) - and their principal receptors - CXCR4 (C-X-C motif receptor 4), CCR2 (C-C motif receptor 2) and CX3CR1 (C-X-3C motif receptor 1), respectively. We first introduce the classification of chemokines and their G-protein coupled receptors and the main signaling pathways triggered by receptor activation. We then discuss the cellular distribution of CXCL12/CXCR4, CCL2/CCR2 and CX3CL1/CX3CR1 in adult brain and the neurotransmission and neuromodulation effects controlled by these chemokines in the adult CNS. Changes in the expression of CXCL12, CCL2 and CX3CL1 and their respective receptors are also increasingly being implicated in the pathogenesis of CNS disorders, such as Alzheimer's disease, Parkinson's disease, HIV-associated encephalopathy, stroke and multiple sclerosis, and are therefore plausible targets for future pharmacological intervention. The final section thus discusses the role of these chemokines in these pathophysiological states. In conclusion, the role of these chemokines in cellular communication may make it possible: i) to identify new pathways of neuron-neuron, glia-glia or neuron-glia communications relevant to both normal brain function and neuroinflammatory and neurodegenerative diseases; ii) to develop new therapeutic approaches for currently untreatable brain diseases.
  Progress in Neurobiology 02/2013;
• Article: From fixed points to chaos: Three models of delayed discrimination.

  Omri Barak, David Sussillo, Ranulfo Romo, Misha Tsodyks, L F Abbott
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  ABSTRACT: Working memory is a crucial component of most cognitive tasks. Its neuronal mechanisms are still unclear despite intensive experimental and theoretical explorations. Most theoretical models of working memory assume both time-invariant neural representations and precise connectivity schemes based on the tuning properties of network neurons. A different, more recent class of models assumes randomly connected neurons that have no tuning to any particular task, and bases task performance purely on adjustment of network readout. Intermediate between these schemes are networks that start out random but are trained by a learning scheme. Experimental studies of a delayed vibrotactile discrimination task indicate that some of the neurons in prefrontal cortex are persistently tuned to the frequency of a remembered stimulus, but the majority exhibit more complex relationships to the stimulus that vary considerably across time. We compare three models, ranging from a highly organized linear attractor model to a randomly connected network with chaotic activity, with data recorded during this task. The random network does a surprisingly good job of both performing the task and matching certain aspects of the data. The intermediate model, in which an initially random network is partially trained to perform the working memory task by tuning its recurrent and readout connections, provides a better description, although none of the models matches all features of the data. Our results suggest that prefrontal networks may begin in a random state relative to the task and initially rely on modified readout for task performance. With further training, however, more tuned neurons with less time-varying responses should emerge as the networks become more structured.
  Progress in Neurobiology 02/2013;
• Article: Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7.

  Udo Rüb, Ludger Schöls, Henry Paulson, Georg Auburger, Pawel Kermer, Joanna C Jen, Kay Seidel, Horst-Werner Korf, Thomas Deller
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  ABSTRACT: The spinocerebellar ataxias type 1 (SCA1), 2 (SCA2), 3 (SCA3), 6 (SCA6) and 7 (SCA7) are genetically defined autosomal dominantly inherited progressive cerebellar ataxias (ADCAs). They belong to the group of CAG-repeat or polyglutamine diseases and share pathologically expanded and meiotically unstable glutamine-encoding CAG-repeats at distinct gene loci encoding elongated polyglutamine stretches in the disease proteins. In recent years, progress has been made in the understanding of the pathogenesis of these currently incurable diseases: Identification of underlying genetic mechanisms made it possible to classify the different ADCAs and to define their clinical and pathological features. Furthermore, advances in molecular biology yielded new insights into the physiological and pathophysiological role of the gene products of SCA1, SCA2, SCA3, SCA6 and SCA7 (i.e. ataxin-1, ataxin-2, ataxin-3, α-1A subunit of the P/Q type voltage-dependent calcium channel, ataxin-7). In the present review we summarize our current knowledge about the polyglutamine ataxias SCA1, SCA2, SCA3, SCA6 and SCA7 and compare their clinical and electrophysiological features, genetic and molecular biological background, as well as their brain pathologies. Furthermore, we provide an overview of the structure, interactions and functions of the different disease proteins. On the basis of these comprehensive data, similarities, differences and possible disease mechanisms are discussed.
  Progress in Neurobiology 02/2013;
• Article: Prevention of chronic postoperative pain: Cellular, molecular, and clinical insights for mechanism-based treatment approaches.

  Ronald Deumens, Arnaud Steyaert, Patrice Forget, Michael Schubert, Patricia Lavand'homme, Emmanuel Hermans, Marc De Kock
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  ABSTRACT: Nearly every surgery can elicit a rather therapy-resistant chronic postoperative pain. Preventive medicine is therefore anticipated with hopeful eyes, but requires a better understanding of the neurobiological mechanisms underlying the transition from acute to chronic pain. Spinal mechanisms of pain amplification are regarded as fundamental to pain chronification, but these mechanisms on their own are not at all likely to be sufficient. Indeed, not every surgical patient develops chronic postoperative pain. Progress in our neurobiological understanding of postoperative pain includes scientific discoveries of 'vulnerability factors', which substantially impact on the spinal cord, augmenting pain amplification mechanisms, perhaps to levels of no-return. In this review we elaborate on spinal pain amplification mechanisms in relation to pain chronification and the impact of vulnerability factors hereon. Moreover, these insights are incorporated within a clinical frame of treatment approaches currently used in surgical settings. As such, this review provides an integrated overview of mechanism-based treatment approaches in prevention of chronic postoperative pain.
  Progress in Neurobiology 02/2013;
• Article: A Conceptual Framework and Ethics Analysis for Prevention Trials of Alzheimer Disease.

  Kevin R Peters, B Lynn Beattie, Howard H Feldman, Judy Illes
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  ABSTRACT: As our understanding of the neurobiology of Alzheimer Disease deepens, it has become evident that early intervention is critical to achieving successful therapeutic impact. The availability of diagnostic criteria for preclinical Alzheimer Disease adds momentum to research directed at this goal and even to prevention. The landscape of therapeutic research is thus poised to undergo a dramatic shift in the next 5-10 years, with clinical trials involving subjects at risk for Alzheimer Disease who have few or no symptoms. These trials will also likely rely heavily on genetics, biomarkers, and or risk factor stratification to identify individuals at risk for Alzheimer Disease. Here, we propose a conceptual framework to guide this next generation of pharmacological and non-pharmacological clinical pursuit, and discuss some of the foreseeable ethical considerations that may accompany them.
  Progress in Neurobiology 01/2013;
• Article: Ischemic Stroke and Traumatic Brain Injury: The Role of the Kallikrein-Kinin System.

  Christiane Albert-Weißenberger, Anna-Leena Sirén, Christoph Kleinschnitz
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  ABSTRACT: Acute ischemic stroke and traumatic brain injury are a major cause of mortality and morbidity. Due to the paucity of therapies, there is a pressing clinical demand for new treatment options. Successful therapeutic strategies for these conditions must target multiple pathophysiological mechanisms occurring at different stages of brain injury. In this respect, the kallikrein-kinin system is an ideal target linking key pathological hallmarks of ischemic and traumatic brain damage such as edema formation, inflammation, and thrombosis. In particular, the kinin receptors, plasma kallikrein, and coagulation factor XIIa are highly attractive candidates for pharmacological development, as kinin receptor antagonists or inhibitors of plasma kallikrein and coagulation factor XIIa are neuroprotective in animal models of stroke and traumatic brain injury. Nevertheless, conflicting preclinical evaluation as well as limited and inconclusive data from clinical trials suggest caution when transferring observations made in animals into the human situation. This review summarizes current evidence on the pathological significance of the kallikrein-kinin system during ischemic and traumatic brain damage, with a particular focus on experimental data derived from animal models. Experimental findings are also compared with human data if available, and potential therapeutic implications are discussed.
  Progress in Neurobiology 12/2012;
• Article: Viral models of multiple sclerosis: Neurodegeneration and demyelination in mice infected with Theilers virus.

  Miriam Mecha, Francisco J Carrillo-Salinas, Leyre Mestre, Ana Feliú, Carmen Guaza
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  ABSTRACT: Multiple sclerosis (MS) is a complex inflammatory disease of unknown etiology that affects the central nervous system (CNS) white matter, and for which no effective cure exists. Indeed, whether the primary event in MS pathology affects myelin or axons of the CNS remains unclear. Animal models are necessary to identify the immunopathological mechanisms involved in MS and to develop novel therapeutic and reparative approaches. Specifically, viral models of chronic demyelination and axonal damage have been used to study the contribution of viruses in human MS, and they have led to important breakthroughs in our understanding of MS pathology. The Theiler's murine encephalomyelitis virus (TMEV) model is one of the most commonly used MS models, although other viral models are also used, including neurotropic strains of mouse hepatitis virus (MHV) that induce chronic inflammatory demyelination with similar histological features to those observed in MS. This review will discuss the immunopathological mechanisms involved in TMEV-induced demyelinating disease (TMEV-IDD). The TMEV model reproduces a chronic progressive disease due to the persistence of the virus for the entire lifespan in susceptible mice. The evolution and significance of the axonal damage and neuroinflammation, the importance of epitope spread from viral to myelin epitopes, the presence of abortive remyelination and the existence of a brain pathology in addition to the classical spinal cord demyelination, are some of the findings that will be discussed in the context of this TMEV-IDD model. Despite their limitations, viral models remain an important tool to study the etiology of MS, and to understand the clinical and pathological variability associated with this disease.
  Progress in Neurobiology 11/2012;
• Article: Barrel Cortex Function.

  Dirk Feldmeyer, Michael Brecht, Fritjof Helmchen, Carl C H Petersen, James F A Poulet, Jochen F Staiger, Heiko J Luhmann, Cornelius Schwarz
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  ABSTRACT: Neocortex, the neuronal structure at the base of the remarkable cognitive skills of mammals, is a layered sheet of neuronal tissue composed of juxtaposed and interconnected columns. A cortical column is considered the basic module of cortical processing present in all cortical areas. It is believed to contain a characteristic microcircuit composed of a few thousands of neurons. The high degree of cortical segmentation into vertical columns and horizontal layers is a boon for scientific investigation because it eases the systematic dissection and functional analysis of intrinsic as well as extrinsic connections of the column. In this review we will argue that in order to understand neocortical function one needs to combine a microscopic view, elucidating the workings of the local columnar microcircuits, with a macroscopic view, which keeps track of the linkage of distant cortical modules in different behavioral contexts. We will exemplify this strategy using the model system of vibrissal touch in mice and rats. On the macroscopic level vibrissal touch is an important sense for the subterranean rodents and has been honed by evolution to serve an array of distinct behaviors. Importantly, the vibrissae are moved actively to touch - requiring intricate sensorimotor interactions. Vibrissal touch, therefore, offers ample opportunities to relate different behavioral contexts to specific interactions of distant columns. On the microscopic level, the cortical modules in primary somatosensory cortex process touch inputs at highest magnification and discreteness - each whisker is represented by its own so-called barrel column. The cellular composition, intrinsic connectivity and functional aspects of the barrel column have been studied in great detail. Building on the versatility of genetic tools available in rodents, new, highly selective and flexible cellular and molecular tools to monitor and manipulate neuronal activity have been devised. Researchers have started to combine these with advanced and highly precise behavioral methods, on par with the precision known from monkey preparations. Therefore, the vibrissal touch model system is exquisitely positioned to combine the microscopic with the macroscopic view and promises to be instrumental in our understanding of neocortical function.
  Progress in Neurobiology 11/2012;
• Article: Fig4 Deficiency: A Newly Emerged Lysosomal Storage Disorder?

  Colin Martyn, Jun Li
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  ABSTRACT: FIG4 (Sac3 in mammals) is a 5'-phosphoinositide phosphatase that coordinates the turnover of phosphatidylinositol-3,5-bisphosphate (PI(3,5)P(2)), a very low abundance phosphoinositide. Deficiency of FIG4 severely affects the human and mouse nervous systems by causing two distinct forms of abnormal lysosomal storage. The first form occurs in spinal sensory neurons, where vacuolated endolysosomes accumulate in perinuclear regions. A second form occurs in cortical/spinal motor neurons and glia, in which enlarged endolysosomes become filled with electron dense materials in a manner indistinguishable from other lysosomal storage disorders. Humans with a deficiency of FIG4 (known as Charcot-Marie-Tooth disease type 4J or CMT4J) present with clinical and pathophysiological phenotypes indicative of spinal motor neuron degeneration and segmental demyelination. These findings reveal a signaling pathway involving FIG4 that appears to be important for lysosomal function. In this review, we discuss the biology of FIG4 and describe how the deficiency of FIG4 results in lysosomal phenotypes. We also discuss the implications of FIG4/PI(3,5)P(2) signaling in understanding other lysosomal storage diseases, neuropathies, and acquired demyelinating diseases.
  Progress in Neurobiology 11/2012;