Huntington's Diseases Research Articles

Autophagy as an Emerging Common Pathomechanism in Inherited Peripheral Neuropathies.

The inherited peripheral neuropathies (IPNs) comprise a growing list of genetically heterogeneous diseases. With mutations in more than 80 genes being reported to cause IPNs, a wide spectrum of functional consequences is expected to follow this genotypic diversity. Hence, the search for a common pathomechanism among the different phenotypes has become the holy grail of functional research into IPNs. During the last decade, studies on several affected genes have shown a direct and/or indirect correlation with autophagy. Autophagy, a cellular homeostatic process, is required for the removal of cell aggregates, long-lived proteins and dead organelles from the cell in double-membraned vesicles destined for the lysosomes. As an evolutionarily highly conserved process, autophagy is essential for the survival and proper functioning of the cell. Recently, neuronal cells have been shown to be particularly vulnerable to disruption of the autophagic pathway. Furthermore, autophagy has been shown to be affected in various common neurodegenerative diseases of both the central and the peripheral nervous system including Alzheimer’s, Parkinson’s, and Huntington’s diseases. In this review we provide an overview of the genes involved in hereditary neuropathies which are linked to autophagy and we propose the disruption of the autophagic flux as an emerging common pathomechanism. We also shed light on the different steps of the autophagy pathway linked to these genes. Finally, we review the concept of autophagy being a therapeutic target in IPNs, and the possibilities and challenges of this pathway-specific targeting.

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Hereditary sensory and autonomic neuropathy type III, or familial dysautonomia [FD; Online Mendelian Inheritance in Man (OMIM) 223900], affects the development and long-term viability of neurons in the peripheral nervous system (PNS) and retina. FD is caused by a point mutation in the gene IKBKAP/ELP1 that results in a tissue-specific reduction of the IKAP/ELP1 protein, a subunit of the Elongator complex. Hallmarks of the disease include vasomotor and cardiovascular instability and diminished pain and temperature sensation caused by reductions in sensory and autonomic neurons. It has been suggested but not demonstrated that mitochondrial function may be abnormal in FD. We previously generated an Ikbkap/Elp1 conditional-knockout mouse model that recapitulates the selective death of sensory (dorsal root ganglia) and autonomic neurons observed in FD. We now show that in these mice neuronal mitochondria have abnormal membrane potentials, produce elevated levels of reactive oxygen species, are fragmented, and do not aggregate normally at axonal branch points. The small hydroxylamine compound BGP-15 improved mitochondrial function, protecting neurons from dying in vitro and in vivo, and promoted cardiac innervation in vivo. Given that impairment of mitochondrial function is a common pathological component of neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's, Parkinson's, and Huntington's diseases, our findings identify a therapeutic approach that may have efficacy in multiple degenerative conditions.

Brain metabolism in health, aging, andneurodegeneration.

Brain cells normally respond adaptively to bioenergetic challenges resulting from ongoing activity in neuronal circuits, and from environmental energetic stressors such as food deprivation and physical exertion. At the cellular level, such adaptive responses include the "strengthening" of existing synapses, the formation of new synapses, and the production of new neurons from stem cells. At the molecular level, bioenergetic challenges result in the activation of transcription factors that induce the expression of proteins that bolster the resistance of neurons to the kinds of metabolic, oxidative, excitotoxic, and proteotoxic stresses involved in the pathogenesis of brain disorders including stroke, and Alzheimer's and Parkinson's diseases. Emerging findings suggest that lifestyles that include intermittent bioenergetic challenges, most notably exercise and dietary energy restriction, can increase the likelihood that the brain will function optimally and in the absence of disease throughout life. Here, we provide an overview of cellular and molecular mechanisms that regulate brain energy metabolism, how such mechanisms are altered during aging and in neurodegenerative disorders, and the potential applications to brain health and disease of interventions that engage pathways involved in neuronal adaptations to metabolic stress.

Rapid and Refined CD11b Magnetic Isolation of Primary Microglia with Enhanced Purity and Versatility.

Microglia are the primary responders to central nervous system insults; however, much remains unknown about their role in regulating neuroinflammation. Microglia are mesodermal cells that function similarly to macrophages in surveying inflammatory stress. The classical (M1-type) and alternative (M2-type) activations of macrophages have also been extended to microglia in an effort to better understand the underlying interplay these phenotypes have in neuroinflammatory conditions such as Parkinson's, Alzheimer's, and Huntington's Diseases. In vitro experimentation utilizing primary microglia offers rapid and reliable results that may be extended to the in vivo environment. Although this is a clear advantage over in vivo experimentation, isolating microglia while achieving adequate yields of optimal purity has been a challenge. Common methods currently in use either suffer from low recovery, low purity, or both. Herein, we demonstrate a refinement of the column-free CD11b magnetic separation method that achieves a high cell recovery and enhanced purity in half the amount of time. We propose this optimized method as a highly useful model of primary microglial isolation for the purposes of studying neuroinflammation and neurodegeneration.

Purinergic Signalling and Neurological Diseases: An Update.

Purinergic signalling, i.e. ATP as an extracellular signalling molecule and cotransmitter in both peripheral and central neurons, is involved in the physiology of neurotransmission and neuromodulation. Receptors for purines have been cloned and characterised, including 4 subtypes of the P1(adenosine) receptor family, 7 subtypes of the P2X ion channel nucleotide receptor family and 8 subtypes of the P2Y G protein-coupled nucleotide receptor family. The roles of purinergic signalling in diseases of the central nervous system and the potential use of purinergic compounds for their treatment are attracting increasing attention. In this review, the focus is on the findings reported in recent papers and reviews to update knowledge in this field about the involvement of purinergic signalling in Alzheimer's, Parkinson's and Huntington's diseases, multiple sclerosis, amyotrophic lateral sclerosis, degeneration and regeneration after brain injury, stroke, ischaemia, inflammation, migraine, epilepsy, psychiatric disorders, schizophrenia, bipolar disorder, autism, addiction, sleep disorders and brain tumours. The use in particular of P2X7 receptor antagonists for the treatment of neurodegenerative diseases, cancer, depression, stroke and ischaemia, A2A receptor antagonists for Parkinson's disease and agonists for brain injury and depression and P2X3 receptor antagonists for migraine and seizures has been recommended. P2Y receptors have also been claimed to be involved in some central nervous disorders.

A Common Mechanism of Proteasome Impairment by Neurodegenerative Disease‐Associated Oligomers

Neurodegenerative diseases are characterized by an accumulation of misfolded proteins, loss of proteostasis, and the progressive death of neurons. It is well established that the ubiquitin proteasome system (UPS), a major regulator of proteostasis, is impaired in essentially all neurodegenerative diseases. Accordingly, targeted proteasome inhibition in the brain recapitulates many physiological and behavioral hallmarks of neurodegeneration. Several studies have attempted to investigate how the UPS is impaired by protein aggregation, but none of these models provide detailed mechanisms of impairment nor can they be applied to the general spectrum of neurodegenerative diseases. Here, we show that three proteins implicated in Alzheimer's, Parkinson's, and Huntington's diseases form soluble oligomers sharing a similar structure that potently inhibits the proteasome with low nanomolar affinity. These oligomers bind to the 20S proteasome core particle and prevent opening of the substrate‐entry channel, thereby impairing both ubiquitin dependent and independent protein degradation. Mechanistic analysis demonstrates that these oligomers allosterically block a well characterized conformational change in the α‐subunits that is required for substrate entry into the catalytic chamber of the 20S proteasome. Proteasome impairment by these oligomers is expected to accelerate further protein accumulation in a positive feedback loop, thereby contributing to the onset and progression of disease. Our findings suggest that proteasome impairment in many neurodegenerative diseases may have a common mechanism, and identify an excellent target for future drug discovery efforts.Support or Funding InformationThis work was supported by start‐up funds to DMS from West Virginia University and by NIH‐R01GM107129 to DMS.

Exosomes and Homeostatic Synaptic Plasticity Are Linked to Each other and to Huntington's, Parkinson's, and Other Neurodegenerative Diseases by Database-Enabled Analyses of Comprehensively Curated Datasets.

Huntington's disease (HD) is a progressive and autosomal dominant neurodegeneration caused by CAG expansion in the huntingtin gene (HTT), but the pathophysiological mechanism of mutant HTT (mHTT) remains unclear. To study HD using systems biological methodologies on all published data, we undertook the first comprehensive curation of two key PubMed HD datasets: perturbation genes that impact mHTT-driven endpoints and therefore are putatively linked causally to pathogenic mechanisms, and the protein interactome of HTT that reflects its biology. We perused PubMed articles containing co-citation of gene IDs and MeSH terms of interest to generate mechanistic gene sets for iterative enrichment analyses and rank ordering. The HD Perturbation database of 1,218 genes highly overlaps the HTT Interactome of 1,619 genes, suggesting links between normal HTT biology and mHTT pathology. These two HD datasets are enriched for protein networks of key genes underlying two mechanisms not previously implicated in HD nor in each other: exosome synaptic functions and homeostatic synaptic plasticity. Moreover, proteins, possibly including HTT, and miRNA detected in exosomes from a wide variety of sources also highly overlap the HD datasets, suggesting both mechanistic and biomarker links. Finally, the HTT Interactome highly intersects protein networks of pathogenic genes underlying Parkinson's, Alzheimer's and eight non-HD polyglutamine diseases, ALS, and spinal muscular atrophy. These protein networks in turn highly overlap the exosome and homeostatic synaptic plasticity gene sets. Thus, we hypothesize that HTT and other neurodegeneration pathogenic genes form a large interlocking protein network involved in exosome and homeostatic synaptic functions, particularly where the two mechanisms intersect. Mutant pathogenic proteins cause dysfunctions at distinct points in this network, each altering the two mechanisms in specific fashion that contributes to distinct disease pathologies, depending on the gene mutation and the cellular and biological context. This protein network is rich with drug targets, and exosomes may provide disease biomarkers, thus enabling drug discovery. All the curated datasets are made available for other investigators. Elucidating the roles of pathogenic neurodegeneration genes in exosome and homeostatic synaptic functions may provide a unifying framework for the age-dependent, progressive and tissue selective nature of multiple neurodegenerative diseases.

How the shapes of seeds can influence pathology

It is widely accepted that the loss of function of different cellular proteins following their aggregation into highly stable aggregates or the gain of pathologic function of the resulting macromolecular assemblies or both processes are tightly associated to distinct debilitating neurodegenerative diseases such as Alzheimer's, Parkinson's, Creutzfeldt-Jacob, Amyotrophic Lateral Sclerosis and Huntington's diseases. How the aggregation of one given protein leads to distinct diseases is unclear. Here, a structural-molecular explanation based on the ability of proteins such as α-synuclein or tau to form assemblies that differ by their intrinsic architecture, stability, seeding capacity, and surfaces is proposed to account for distinct synucleinopathies and tauopathies. The shape and surfaces of the seeds is proposed to define at the same time their seeding capacity, interactome and tropism for defined neuronal cells within the central nervous system.

Role of STIM2 in cell function and physiopathology.

An endoplasmic reticulum (ER)-resident protein that regulates cytosolic and ER free-Ca2+ concentration by induction of store-operated calcium entry: that is the original definition of STIM2 and its function. While its activity strongly depends on the amount of calcium stored in the ER, its function goes further, to intracellular signalling and gene expression. Initially under-studied owing to the prominent function of STIM1, STIM2 came to be regarded as vital in mice, gradually emerging as an important player in the nervous system, and cooperating with STIM1 in the immune system. STIM2 has also been proposed as a relevant player in pathological conditions related to ageing, Alzheimer's and Huntington's diseases, autoimmune disorders and cancer. The discovery of additional functions, together with new splicing forms with opposite roles, has clarified existing controversies about STIM2 function in SOCE. With STIM2 being essential for life, but apparently not for development, newly available data demonstrate a complex and still intriguing behaviour that this review summarizes, updating current knowledge of STIM2 function.

Mesoscopic Properties and Molecular Mechanisms of IAPP Amyloid Inhibition and Remodeling with Small Molecules

The amyloid aggregation of proteins is associated with a number of neurodegenerative diseases such like Alzheimer's, Huntington's and Parkinson's diseases, and also type-2 diabetes (T2D). Despite the physical and structural properties of the aggregating proteins, the corresponding amyloid aggregates feature some common characteristics including the formation of cross-β architecture and cytotoxicity to human cells, suggesting a common amyloid mechanism. Experimental studies have shown that several naturally-occurring small molecules, such as epigallocatechin gallate (EGCG), have an inhibitory effect on the aggregation of a wide range of those amyloid proteins, including islet amyloid polypeptide (IAPP, a.k.a.

MicroRNAs in Neurocognitive Dysfunctions: New Molecular Targets for Pharmacological Treatments?

BackgroundNeurodegenerative and cognitive disorders are multifactorial diseases (i.e., involving neurodevelopmental, genetic, age or environmental factors) characterized by an abnormal development that affects neuronal function and integrity. Recently, an increasing number of studies revealed that the dysregulation of microRNAs (miRNAs) may be involved in the etiology of cognitive disorders as Alzheimer, Parkinson, and Huntington‘s diseases, Schizophrenia and Autism spectrum disorders.MethodsFrom an extensive search in bibliographic databases of peer-reviewed research literature, we identified relevant published studies related to specific key words such as memory, cognition, neurodegenerative disorders, neurogenesis and miRNA. We then analysed, evaluated and summerized scientific evidences derived from these studies.ResultsWe first briefly summarize the basic molecular events involved in memory, a process inherent to cognitive disease, and then describe the role of miRNAs in neurodevelopment, synaptic plasticity and memory. Secondly, we provide an overview of the impact of miRNA dysregulation in the pathogenesis of different neurocognitive disorders, and lastly discuss the feasibility of miRNA-based therapeutics in the treatment of these disorders.ConclusionThis review highlights the molecular basis of neurodegenerative and cognitive disorders by focusing on the impact of miRNAs dysregulation in these pathological phenotypes. Altogether, the published reports suggest that miRNAs-based therapy could be a viable therapeutic alternative to current treatment options in the future.

Therapeutic potential of α7 nicotinic receptor agonists to regulate neuroinflammation in neurodegenerative diseases.

Neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's diseases, are all characterized by a component of innate immunity called neuroinflammation. Neuronal loss and neuroinflammation are two phenomena closely linked. Hence, the neuroinflammation is a relevant target for the management of the neurodegenerative diseases given that, to date, there is no treatment to stop neuronal loss. Several studies have investigated the potential effects of activators of alpha 7 nicotinic acetylcholine receptors in animal models of neurodegenerative diseases. These receptors are widely distributed in the central nervous system. After activation, they seem to mediate the cholinergic anti-inflammatory pathway in the brain. This anti-inflammatory pathway, first described in periphery, regulates activation of microglial cells considered as the resident macrophage population of the central nervous system. In this article, we shortly review the agonists of the alpha 7 nicotinic acetylcholine receptors that have been evaluated in vivo and we focused on the selective positive allosteric modulators of these receptors. These compounds represent a key element to enhance receptor activity only in the presence of the endogenous agonist.

Taking out the garbage: cathepsin D and calcineurin in neurodegeneration.

Cellular homeostasis requires a tightly controlled balance between protein synthesis, folding and degradation. Especially long-lived, post-mitotic cells such as neurons depend on an efficient proteostasis system to maintain cellular health over decades. Thus, a functional decline of processes contributing to protein degradation such as autophagy and general lysosomal proteolytic capacity is connected to several age-associated neurodegenerative disorders, including Parkinson's, Alzheimer's and Huntington's diseases. These so called proteinopathies are characterized by the accumulation and misfolding of distinct proteins, subsequently driving cellular demise. We recently linked efficient lysosomal protein breakdown via the protease cathepsin D to the Ca2+/calmodulin-dependent phosphatase calcineurin. In a yeast model for Parkinson's disease, functional calcineurin was required for proper trafficking of cathepsin D to the lysosome and for recycling of its endosomal sorting receptor to allow further rounds of shuttling. Here, we discuss these findings in relation to present knowledge about the involvement of cathepsin D in proteinopathies in general and a possible connection between this protease, calcineurin signalling and endosomal sorting in particular. As dysregulation of Ca2+ homeostasis as well as lysosomal impairment is connected to a plethora of neurodegenerative disorders, this novel interplay might very well impact pathologies beyond Parkinson's disease.

Fungal models for amyloids and prions

Statement of the Problem: Prions are alternatively folded self-perpetuating protein isoforms involved in a variety of biological and pathological processes. Most prions are based on self-assembled protein aggregates (amyloids). In humans, amyloids and prions are associated with important diseases, such as Alzheimer, Parkinson and Huntington diseases, and transmissible spongiform encephalopathies. In yeast and other fungi, prions are protein-based non-Mendelian elements that control heritable traits. Methodology & Theoretical Orientation: Due to relative simplicity of cultivation procedures and availability of convenient phenotypic assays, fungi provide a great opportunity for deciphering the general mechanisms of the formation and propagation of amyloids and prions. Findings: Yeast and fungal prions influence a variety of physiological functions. Prion formation and loss are modulated by environmental and physiological conditions. De novo formation of an yeast prion can be induced by a transient overproduction of a prion-forming protein. The process of prion formation includes generation of the intermediate aggregated structures, associated with cytoskeletal networks and quality control compartments. Propagation of yeast prions is controlled by the same cytosolic Hsp104/70/40 chaperone machinery that is involved in protection of yeast cells against proteotoxic stress. Chaperones fragment prion polymers thus providing oligomeric seeds for new rounds of prion propagation. Ribosome-associated chaperones antagonize prion formation and interfere with the ability of cytosolic chaperones to promote prion propagation. Chaperone and cytoskeletal machineries mediate effects of environmental stresses on prions. Conclusion & Significance: The impact of prions on fungal biology is still underestimated. An intimate relationship with the protein quality control machinery of the cell plays a key role in the processes of prion formation and propagation in yeast. Many components of this machinery possess homologs or functional counterparts in higher eukaryotes, thus making yeast prions an excellent model for deciphering the general mechanisms of amyloid/prion formation and propagation in norm and pathology.

Functional role of new striatopallidal specific genes in motor and motivational behavior

Event Abstract Back to Event Functional role of new striatopallidal specific genes in motor and motivational behavior Deniz Karadurmus1*, Daniel Rial1, Alban De Kerchove D'Exaerde1 and Serge N. Schiffmann1 1 Université Libre de Bruxelles, Belgium Basal ganglia are a set of interconnected nuclei involved in motor control and motivation. The striatum is the main input of basal ganglia and is mainly composed of medium spiny neurons, subdivided into striatopallidal (STP) and striatonigral (STN) neurons. STP and STN neurons give rise respectively to the indirect and the direct pathways of basal ganglia, with opposite effects at both motor and motivational levels. Cellular mechanisms involving these pathways in disorders such as Huntington's and Parkinson's diseases and addiction, are still poorly understood. Our laboratory has previously identified gene expression profiles of STN and STP neurons using microarray (Ena et al., 2013). The present work consists in the identification and functional study of genes differentially expressed in STN and STP neurons, selected on their potential involvement in striatal functions. Using floxed mice, shRNA interference mediated by lentivirus and CRISPR/Cas9 techniques, we generated knockdown and/or knockout models for these genes. We are now assessing the effect of gene deletion using a multi technique approach, combining 3D reconstruction, electrophysiology and behavioral tests. Acknowledgements D.K.. was supported by a Research Fellow grant of the Fonds National de la Recherche Scientifique (FRS-FNRS) (Belgium). Keywords: Striatum, striatopallidal pathway, cell-type-specific gene, knockdown model, striatonigral pathway Conference: 12th National Congress of the Belgian Society for Neuroscience, Gent, Belgium, 22 May - 22 May, 2017. Presentation Type: Poster Presentation Topic: Cognition and Behavior Citation: Karadurmus D, Rial D, De Kerchove D'Exaerde A and Schiffmann SN (2019). Functional role of new striatopallidal specific genes in motor and motivational behavior. Front. Neurosci. Conference Abstract: 12th National Congress of the Belgian Society for Neuroscience. doi: 10.3389/conf.fnins.2017.94.00074 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 24 Apr 2017; Published Online: 25 Jan 2019. * Correspondence: Ms. Deniz Karadurmus, Université Libre de Bruxelles, Brussels, Belgium, denizkaradurmus@hotmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Deniz Karadurmus Daniel Rial Alban De Kerchove D'Exaerde Serge N Schiffmann Google Deniz Karadurmus Daniel Rial Alban De Kerchove D'Exaerde Serge N Schiffmann Google Scholar Deniz Karadurmus Daniel Rial Alban De Kerchove D'Exaerde Serge N Schiffmann PubMed Deniz Karadurmus Daniel Rial Alban De Kerchove D'Exaerde Serge N Schiffmann Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Metal complexes for multimodal imaging of misfolded protein-related diseases.

Aggregation of misfolded proteins and progressive polymerization of otherwise soluble proteins is a common hallmark of a wide range of highly debilitating and increasingly prevalent diseases, including amyotrophic lateral sclerosis, cerebral amyloid angiopathy, type II diabetes and Parkinson's, Huntington's and Alzheimer's diseases. There is a growing interest in creating imaging agents to detect such aggregates in various imaging modalities, including PET, SPECT and MRI. We present here an overview of recent efforts from the perspective of early diagnosis of amyloid diseases, with a major focus on Aβ detection and metal complexes bearing PiB units.

Insights into the mechanisms of copper dyshomeostasis in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a severe neuromuscular disease characterised by a progressive loss of motor neurons that usually results in paralysis and death within 2 to 5 years after disease onset. The pathophysiological mechanisms involved in ALS remain largely unknown and to date there is no effective treatment for this disease. Here, we review clinical and experimental evidence suggesting that dysregulation of copper homeostasis in the central nervous system is a crucial underlying event in motor neuron degeneration and ALS pathophysiology. We also review and discuss novel approaches seeking to target copper delivery to treat ALS. These novel approaches may be clinically relevant not only for ALS but also for other neurological disorders with abnormal copper homeostasis, such as Parkinson's, Huntington's and Prion diseases.

Glucose Transporters in Brain: In Health and in Alzheimer's Disease.

Neurons need a continuous supply of glucose, the major source of energy for mammalian brain metabolism. The central nervous system is protected by three main physiological cell barriers. Cell membranes are impermeable for glucose, therefore glucose is transferred across the cell membranes by specific transport proteins: sodium-independent glucose transporters (GLUTs), encoded by SLC2 genes, and sodium-dependent glucose transporters (for example SGLTs), encoded by SLC5 genes. Human brain expresses 10 GLUT proteins and 10 proteins encoded by SLC5 genes. In patients with brain diseases, particularly Alzheimer's (AD) and Huntington's diseases, abnormalities in neuronal glucose metabolism have been showed. The levels of GLUT1 and GLUT3, the major brain glucose transporters, are decreased, especially in the cerebral cortex. Therefore, in AD, hypometabolism of glucose and deficits in energy are observed. Production of ATP from glucose metabolism in sporadic AD declines to 50% and the tendency to decline continues throughout the progression of the disease. This decrease is correlated with O-GlcAcetylation and tau hyperphosphorylation, as the compensatory mechanisms in AD are the utilization of endogenous brain substances and drastic increase in GLUT2 levels. The present review focuses on the changes in the expression of glucose transporters due to AD.

KymoAnalyzer: a software tool for the quantitative analysis of intracellular transport in neurons.

In axons, proper localization of proteins, vesicles, organelles, and other cargoes is accomplished by the highly regulated coordination of kinesins and dyneins, molecular motors that bind to cargoes and translocate them along microtubule (MT) tracks. Impairment of axonal transport is implicated in the pathogenesis of multiple neurodegenerative disorders including Alzheimer's and Huntington's diseases. To understand how MT-based cargo motility is regulated and to delineate its role in neurodegeneration, it is critical to analyze the detailed dynamics of moving cargoes inside axons. Here, we present KymoAnalyzer, a software tool that facilitates the robust analysis of axonal transport from time-lapse live-imaging sequences. KymoAnalyzer is an open-source software that automatically classifies particle trajectories and systematically calculates velocities, run lengths, pauses, and a wealth of other parameters that are characteristic of motor-based transport. We anticipate that laboratories will easily use this package to unveil previously uncovered intracellular transport details of individually-moving cargoes inside neurons.

Neurotrophin signalling: novel insights into mechanisms and pathophysiology.

Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are prominent regulators of neuronal survival, growth and differentiation during development. While trophic factors are viewed as well-understood but not innovative molecules, there are many lines of evidence indicating that BDNF plays an important role in the pathophysiology of many neurodegenerative disorders, depression, anxiety and other psychiatric disorders. In particular, lower levels of BDNF are associated with the aetiology of Alzheimer's and Huntington's diseases. A major challenge is to explain how neurotrophins are able to induce plasticity, improve learning and memory and prevent age-dependent cognitive decline through receptor signalling. This article will review the mechanism of action of neurotrophins and how BDNF/tropomyosin receptor kinase B (TrkB) receptor signaling can dictate trophic responses and change brain plasticity through activity-dependent stimulation. Alternative approaches for modulating BDNF/TrkB signalling to deliver relevant clinical outcomes in neurodegenerative and neuropsychiatric disorders will also be described.