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| 2. |
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| 3. |
- Aufschnaiter, Andreas, et al.
(författare)
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Taking out the garbage : cathepsin D and calcineurin in neurodegeneration
- 2017
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Ingår i: Neural Regeneration Research. - : Medknow. - 1673-5374 .- 1876-7958. ; 12:11, s. 1776-1779
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Forskningsöversikt (refereegranskat)abstract
- 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.
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| 4. |
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| 5. |
- Ching, Rosanna C., et al.
(författare)
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The role of exosomes in peripheral nerve regeneration
- 2015
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Ingår i: Neural Regeneration Research. - : Medknow. - 1673-5374 .- 1876-7958. ; 10:5, s. 743-747
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Forskningsöversikt (refereegranskat)abstract
- Peripheral nerve injuries remain problematic to treat, with poor functional recovery commonly observed. Injuries resulting in a nerve gap create specific difficulties for axonal regeneration. Approaches to address these difficulties include autologous nerve grafts (which are currently the gold standard treatment) and synthetic conduits, with the latter option being able to be impregnated with Schwann cells or stem cells which provide an appropriate micro-environment for neuronal regeneration to occur. Transplanting stem cells, however, infers additional risk of malignant transformation as well as manufacturing difficulties and ethical concerns, and the use of autologous nerve grafts and Schwann cells requires the sacrifice of a functioning nerve. A new approach utilizing exosomes, secreted extracellular vesicles, could avoid these complications. In this review, we summarize the current literature on exosomes, and suggest how they could help to improve axonal regeneration following peripheral nerve injury.
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| 8. |
- Latini, Francesco, 1982-, et al.
(författare)
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Rethinking the standard trans-cortical approaches in the light of superficial white matter anatomy
- 2015
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Ingår i: Neural Regeneration Research. - Meadows : Medknow. - 1673-5374 .- 1876-7958. ; 10:12, s. 1906-1909
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Forskningsöversikt (refereegranskat)abstract
- A better comprehension of the superficial white matter organization is important in order to minimize potential and avoidable damage to long or intermediate association fibre bundles during every step of a surgical approach. We recently proposed a technique for cadaver specimen preparation, which seems able to identify a more systematic organization of the superficial white matter terminations. Moreover, the use of the physiological intracranial vascular network for the fixation process allowed us to constantly show main vascular landmarks associated with white matter structures. Hence three examples of standard approaches to eloquent areas are herein reanalyzed starting from the first superficial layer. New insights into the possible surgical trajectories and subsequent quantitative damages of both vessels and white matter fibres can help readapt even the most standard and widely accepted approach trough the brain cortex. A more detailed study of these fine anatomical details may become in the near future a fundamental part of the neurosurgical training and the preoperative planning.
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| 9. |
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| 10. |
- Moulin, Thiago, et al.
(författare)
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Dendritic spine density changes and homeostatic synaptic scaling : a meta-analysis of animal studies
- 2022
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Ingår i: Neural Regeneration Research. - : Medknow. - 1673-5374 .- 1876-7958. ; 17:1, s. 20-24
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Tidskriftsartikel (refereegranskat)abstract
- Mechanisms of homeostatic plasticity promote compensatory changes of cellular excitability in response to chronic changes in the network activity. This type of plasticity is essential for the maintenance of brain circuits and is involved in the regulation of neural regeneration and the progress of neurodegenerative disorders. One of the most studied homeostatic processes is synaptic scaling, where global synaptic adjustments take place to restore the neuronal firing rate to a physiological range by the modulation of synaptic receptors, neurotransmitters, and morphology. However, despite the comprehensive literature on the electrophysiological properties of homeostatic scaling, less is known about the structural adjustments that occur in the synapses and dendritic tree. In this study, we performed a meta-analysis of articles investigating the effects of chronic network excitation (synaptic downscaling) or inhibition (synaptic upscaling) on the dendritic spine density of neurons. Our results indicate that spine density is consistently reduced after protocols that induce synaptic scaling, independent of the intervention type. Then, we discuss the implication of our findings to the current knowledge on the morphological changes induced by homeostatic plasticity.
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| 11. |
- Picca, Anna, et al.
(författare)
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Circulating extracellular vesicles : friends and foes in neurodegeneration
- 2022
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Ingår i: Neural Regeneration Research. - : Medknow. - 1673-5374 .- 1876-7958. ; 17:3, s. 534-542
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Forskningsöversikt (refereegranskat)abstract
- Extracellular vesicles have been identified as pivotal mediators of intercellular communication with critical roles in physiological and pathological conditions. Via this route, several molecules (e.g., nucleic acids, proteins, metabolites) can be transferred to proximal and distant targets to convey specific information. Extracellular vesicle-associated cargo molecules have been proposed as markers of several disease conditions for their potential of tracking down the generating cell. Indeed, circulating extracellular vesicles may represent biomarkers of dysfunctional cellular quality control systems especially in conditions characterized by the accrual of intracellular misfolded proteins. Furthermore, the identification of extracellular vesicles as tools for the delivery of nucleic acids or other cargo molecules to diseased tissues makes these circulating shuttles possible targets for therapeutic development. The increasing interest in the study of extracellular vesicles as biomarkers resides mainly in the fact that the identification of peripheral levels of extracellular vesicle-associated proteins might reflect molecular events occurring in hardly accessible tissues, such as the brain, thereby serving as a “brain liquid biopsy”. The exploitation of extracellular vesicles for diagnostic and therapeutic purposed might offer unprecedented opportunities to develop personalized approaches. Here, we discuss the bright and dark sides of extracellular vesicles in the setting of two main neurodegenerative diseases (i.e., Parkinson’s and Alzheimer’s diseases). A special focus will be placed on the possibility of using extracellular vesicles as biomarkers for the two conditions to enable disease tracking and treatment monitoring.
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| 12. |
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| 13. |
- Rodriguez, Juan, 1983, et al.
(författare)
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Role of apoptosis-inducing factor in perinatal hypoxic-ischemic brain injury
- 2021
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Ingår i: Neural Regeneration Research. - : Medknow. - 1673-5374 .- 1876-7958. ; 16:2, s. 205-213
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Tidskriftsartikel (refereegranskat)abstract
- Perinatal complications, such as asphyxia, can cause brain injuries that are often associated with subsequent neurological deficits, such as cerebral palsy or mental retardation. The mechanisms of perinatal brain injury are not fully understood, but mitochondria play a prominent role not only due to their central function in metabolism but also because many proteins with apoptosis-related functions are located in the mitochondrion. Among these proteins, apoptosis-inducing factor has already been shown to be an important factor involved in neuronal cell death upon hypoxia-ischemia, but a better understanding of the mechanisms behind these processes is required for the development of more effective treatments during the early stages of perinatal brain injury. In this review, we focus on the molecular mechanisms of hypoxic-ischemic encephalopathy, specifically on the importance of apoptosis-inducing factor. The relevance of apoptosis-inducing factor is based not only because it participates in the caspase-independent apoptotic pathway but also because it plays a crucial role in mitochondrial energetic functionality, especially with regard to the maintenance of electron transport during oxidative phosphorylation and in oxidative stress, acting as a free radical scavenger. We also discuss all the different apoptosis-inducing factor isoforms discovered, focusing especially on apoptosis-inducing factor 2, which is only expressed in the brain and the functions of which are starting now to be clarified. Finally, we summarized the interaction of apoptosis-inducing factor with several proteins that are crucial for both apoptosis-inducing factor functions (prosurvival and pro-apoptotic) and that are highly important in order to develop promising therapeutic targets for improving outcomes after perinatal brain injury.
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| 14. |
- Segura-Aguilar, Juan, et al.
(författare)
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Astrocytes protect dopaminergic neurons against aminochrome neurotoxicity
- 2022
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Ingår i: Neural Regeneration Research. - : Medknow. - 1673-5374 .- 1876-7958. ; 17:9, s. 1861-1866
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Forskningsöversikt (refereegranskat)abstract
- Astrocytes protect neurons by modulating neuronal function and survival. Astrocytes support neurons in several ways. They provide energy through the astrocyte-neuron lactate shuttle, protect neurons from excitotoxicity, and internalize neuronal lipid droplets to degrade fatty acids for neuronal metabolic and synaptic support, as well as by their high capacity for glutamate uptake and the conversion of glutamate to glutamine. A recent reported astrocyte system for protection of dopamine neurons against the neurotoxic products of dopamine, such as aminochrome and other o-quinones, were generated under neuromelanin synthesis by oxidizing dopamine catechol structure. Astrocytes secrete glutathione transferase M2-2 through exosomes that transport this enzyme into dopaminergic neurons to protect these neurons against aminochrome neurotoxicity. The role of this new astrocyte protective mechanism in Parkinson´s disease is discussed.
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| 15. |
- Xu, Yiran, et al.
(författare)
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Genetic pathways in cerebral palsy: a review of the implications for precision diagnosis and understanding disease mechanisms
- 2024
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Ingår i: NEURAL REGENERATION RESEARCH. - 1673-5374 .- 1876-7958. ; 19:7, s. 1499-1508
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Forskningsöversikt (refereegranskat)abstract
- Cerebral palsy is a diagnostic term utilized to describe a group of permanent disorders affecting movement and posture. Patients with cerebral palsy are often only capable of limited activity, resulting from non-progressive disturbances in the fetal or neonatal brain. These disturbances severely impact the child's daily life and impose a substantial economic burden on the family. Although cerebral palsy encompasses various brain injuries leading to similar clinical outcomes, the understanding of its etiological pathways remains incomplete owing to its complexity and heterogeneity. This review aims to summarize the current knowledge on the genetic factors influencing cerebral palsy development. It is now widely acknowledged that genetic mutations and alterations play a pivotal role in cerebral palsy development, which can be further influenced by environmental factors. Despite continuous research endeavors, the underlying factors contributing to cerebral palsy remain are still elusive. However, significant progress has been made in genetic research that has markedly enhanced our comprehension of the genetic factors underlying cerebral palsy development. Moreover, these genetic factors have been categorized based on the identified gene mutations in patients through clinical genotyping, including thrombosis, angiogenesis, mitochondrial and oxidative phosphorylation function, neuronal migration, and cellular autophagy. Furthermore, exploring targeted genotypes holds potential for precision treatment. In conclusion, advancements in genetic research have substantially improved our understanding of the genetic causes underlying cerebral palsy. These breakthroughs have the potential to pave the way for new treatments and therapies, consequently shaping the future of cerebral palsy research and its clinical management. The investigation of cerebral palsy genetics holds the potential to significantly advance treatments and management strategies. By elucidating the underlying cellular mechanisms, we can develop targeted interventions to optimize outcomes. A continued collaboration between researchers and clinicians is imperative to comprehensively unravel the intricate genetic etiology of cerebral palsy.
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| 16. |
- Mårdh, Selina
(författare)
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Weak central coherence in patients with Alzheimer’s disease
- 2013
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Ingår i: Neural Regeneration Research. - 1673-5374 .- 1876-7958. ; 8:8, s. 760-766
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Tidskriftsartikel (refereegranskat)abstract
- Central coherence refers to the ability to interpret details of information into a whole. To date, the concept of central coherence is mainly used in research of autism, Asperger’s syndrome and recently in the research on eating disorders. The main purpose of the present study was to examine central coherence in patients with Alzheimer’s disease. Nine Alzheimer’s disease patients and ten age- and gender-matched control subjects, who differed significantly in neurological assessment, were shown a picture of a fire. Compared to control subjects, the Alzheimer’s disease patients described the picture in a fragmented way by mentioning details and separate objects without perceiving the context of the fire. In conclusion, patients with Alzheimer’s disease are at the weak end of central coherence, and hence suffer from a fragmented view of their surroundings. The findings have important clinical implications for the understanding of patients with Alzheimer’s diseaseand also for the possibility of caregivers to meet the Alzheimer’s disease individual in an appropriate way in the everyday care.
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| 17. |
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| 18. |
- Martins, Ana, et al.
(författare)
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Changes in social emotion recognition following traumatic frontal lobe injury
- 2012
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Ingår i: Neural Regeneration Research. - 1673-5374 .- 1876-7958. ; 7:2, s. 101-108
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Tidskriftsartikel (refereegranskat)abstract
- Changes in social and emotional behaviour have been consistently observed in patients withtraumatic brain injury. These changes are associated with emotion recognition deficits whichrepresent one of the major barriers to a successful familiar and social reintegration. In the presentstudy, 32 patients with traumatic brain injury, involving the frontal lobe, and 41 age- andeducation-matched healthy controls were analyzed. A Go/No-Go task was designed, where eachparticipant had to recognize faces representing three social emotions (arrogance, guilt andjealousy). Results suggested that ability to recognize two social emotions (arrogance and jealousy)was significantly reduced in patients with traumatic brain injury, indicating frontal lesion can reduceemotion recognition ability. In addition, the analysis of the results for hemispheric lesion location(right, left or bilateral) suggested the bilateral lesion sub-group showed a lower accuracy on allsocial emotions.
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| 19. |
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| 20. |
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| 21. |
- Mårtensson, Lisa B., et al.
(författare)
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Ca2+ involvement in activation of extracellular-signalregulated- kinase 1/2 and m-calpain after axotomy of the sciatic nerve
- 2017
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Ingår i: Neural Regeneration Research. - : Medknow. - 1673-5374. ; 12:4, s. 623-628
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Tidskriftsartikel (refereegranskat)abstract
- Detailed mechanisms behind regeneration after nerve injury, in particular signal transduction and the fate of Schwann cells (SCs), are poorly understood. Here, we investigated axotomy-induced activation of extracellular- signal-regulated kinase-1/2 (ERK1/2; important for proliferation) and m-calpain in vitro, and the relation to Ca2+ deletion and Schwann cell proliferation and death after rat sciatic nerve axotomy. Nerve segments were cultured for up to 72 hours with and without ethylene glycol-bis(β-aminoethyl ether)- N,N,N’,N’-tetraacetic acid (EGTA). In some experiments, 5-bromo-2′-deoxyuridine (BrdU) was added during the last 24 hours to detect proliferating cells and propidium iodide (PI) was added at the last hour to detect dead and/or dying cells. Immunohistochemistry of sections of the cultured nerve segments was performed to label m-calpain and the phosphorylated and activated form of ERK1/2. The experiments revealed that immunoreactivity for p-ERK1/2 increased with time in organotypically cultured SCs. p-ERK1/2 and m-calpain were also observed in axons. A significant increase in the number of dead or dying SCs was observed in nerve segments cultured for 24 hours. When deprived of Ca2+, activation of axonal m-calpain was reduced, whereas p-ERK1/2 was increased in SCs. Ca2+ deprivation also significantly reduced the number of proliferating SCs, and instead increased the number of dead or dying SCs. Ca2+ seems to play an important role in activation of ERK1/2 in SCs and in SC survival and proliferation. In addition, extracellular Ca2+ levels are also required for m-calpain activation and up-regulation in axons. Thus, regulation of Ca2+ levels is likely to be a useful method to promote SC proliferation.
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| 22. |
- Zhang, Mengliang
(författare)
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Two-step production of monoamines in monoenzymatic cells in the spinal cord : A different control strategy of neurotransmitter supply?
- 2016
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Ingår i: Neural Regeneration Research. - : Medknow. - 1673-5374. ; 11:12, s. 1904-1909
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Forskningsöversikt (refereegranskat)abstract
- Monoamine neurotransmitters play an important role in the modulation of sensory, motor and autonomic functions in the spinal cord. Although traditionally it is believed that in mammalian spinal cord, monoamine neurotransmitters mainly originate from the brain, accumulating evidence indicates that especially when the spinal cord is injured, they can also be produced in the spinal cord. In this review, I will present evidence for a possible pathway for two-step synthesis of dopamine and serotonin in the spinal cord. Published data from different sources and unpublished data from my own ongoing projects indicate that monoenzymatic cells expressing aromatic L-amino acid decarboxylase (AADC), tyrosine hydroxylase (TH) or tryptophan hydroxylase (TPH) are present in the spinal cord and that these TH and THP cells often lie in close proximity to AADC cells. Prompted by the above evidence, I hypothesize that dopamine and serotonin could be synthesized sequentially in two monoenzymatic cells in the spinal cord via a TH-AADC and a TPH-AADC cascade respectively. The monoamines synthesized through this pathway may compensate for lost neurotransmitters following spinal cord injury and also may play specific roles in the recovery of sensory, motor and autonomic functions.
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| 26. |
- Chandrasekaran, S., et al.
(författare)
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Electrical stimulation and denervated muscles after spinal cord injury
- 2020
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Ingår i: Neural Regeneration Research. - : Medknow. - 1673-5374. ; 15:8, s. 1397-1407
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Tidskriftsartikel (refereegranskat)abstract
- Spinal cord injury (SCI) population with injury below T10 or injury to the cauda equina region is characterized by denervated muscles, extensive muscle atrophy, infiltration of intramuscular fat and formation of fibrous tissue. These morphological changes may put individuals with SCI at higher risk for developing other diseases such as various cardiovascular diseases, diabetes, obesity and osteoporosis. Currently, there is no available rehabilitation intervention to rescue the muscles or restore muscle size in SCI individuals with lower motor neuron denervation. We, hereby, performed a review of the available evidence that supports the use of electrical stimulation in restoration of denervated muscle following SCI. Long pulse width stimulation (LPWS) technique is an upcoming method of stimulating denervated muscles. Our primary objective is to explore the best stimulation paradigms (stimulation parameters, stimulation technique and stimulation wave) to achieve restoration of the denervated muscle. Stimulation parameters, such as the pulse duration, need to be 100-1000 times longer than in innervated muscles to achieve desirable excitability and contraction. The use of electrical stimulation in animal and human models induces muscle hypertrophy. Findings in animal models indicate that electrical stimulation, with a combination of exercise and pharmacological interventions, have proven to be effective in improving various aspects like relative muscle weight, muscle cross sectional area, number of myelinated regenerated fibers, and restoring some level of muscle function. Human studies have shown similar outcomes, identifying the use of LPWS as an effective strategy in increasing muscle cross sectional area, the size of muscle fibers, and improving muscle function. Therefore, displaying promise is an effective future stimulation intervention. In summary, LPWS is a novel stimulation technique for denervated muscles in humans with SCI. Successful studies on LPWS of denervated muscles will help in translating this stimulation technique to the clinical level as a rehabilitation intervention after SCI.
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| 31. |
- Pajares, M. A., et al.
(författare)
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Alexander disease: the road ahead
- 2023
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Ingår i: Neural Regeneration Research. - 1673-5374. ; 18:10, s. 2156-60
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Tidskriftsartikel (refereegranskat)abstract
- Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein, a type III intermediate filament protein expressed in astrocytes. Both early (infantile or juvenile) and adult onsets of the disease are known and, in both cases, astrocytes present characteristic aggregates, named Rosenthal fibers. Mutations are spread along the glial fibrillary acidic protein sequence disrupting the typical filament network in a dominant manner. Although the presence of aggregates suggests a proteostasis problem of the mutant forms, this behavior is also observed when the expression of wild-type glial fibrillary acidic protein is increased. Additionally, several isoforms of glial fibrillary acidic protein have been described to date, while the impact of the mutations on their expression and proportion has not been exhaustively studied. Moreover, the posttranslational modification patterns and/or the protein-protein interaction networks of the glial fibrillary acidic protein mutants may be altered, leading to functional changes that may modify the morphology, positioning, and/or the function of several organelles, in turn, impairing astrocyte normal function and subsequently affecting neurons. In particular, mitochondrial function, redox balance and susceptibility to oxidative stress may contribute to the derangement of glial fibrillary acidic protein mutant-expressing astrocytes. To study the disease and to develop putative therapeutic strategies, several experimental models have been developed, a collection that is in constant growth. The fact that most cases of Alexander disease can be related to glial fibrillary acidic protein mutations, together with the availability of new and more relevant experimental models, holds promise for the design and assay of novel therapeutic strategies.
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| 33. |
- Roda, A. R., et al.
(författare)
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Amyloid-beta peptide and tau protein crosstalk in Alzheimer's disease
- 2022
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Ingår i: Neural Regeneration Research. - : Medknow. - 1673-5374. ; 17:8, s. 1666-1674
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease is a neurodegenerative disease that accounts for most of the 50-million dementia cases worldwide in 2018. A large amount of evidence supports the amyloid cascade hypothesis, which states that amyloid-beta accumulation triggers tau hyperphosphorylation and aggregation in form of neurofibrillary tangles, and these aggregates lead to inflammation, synaptic impairment, neuronal loss, and thus to cognitive decline and behavioral abnormalities. The poor correlation found between cognitive decline and amyloid plaques, have led the scientific community to question whether amyloid-beta accumulation is actually triggering neurodegeneration in Alzheimer's disease. The occurrence of tau neurofibrillary tangles better correlates to neuronal loss and clinical symptoms and, although amyloid-beta may initiate the cascade of events, tau impairment is likely the effector molecule of neurodegeneration. Recently, it has been shown that amyloid-beta and tau cooperatively work to impair transcription of genes involved in synaptic function and, more importantly, that downregulation of tau partially reverses transcriptional perturbations. Despite mounting evidence points to an interplay between amyloid-beta and tau, some factors could independently affect both pathologies. Thus, the dual pathway hypothesis, which states that there are common upstream triggers causing both amyloid-beta and tau abnormalities has been proposed. Among others, the immune system seems to be strongly involved in amyloid-beta and tau pathologies. Other factors, as the apolipoprotein E epsilon 4 isoform has been suggested to act as a link between amyloid-beta and tau hyperphosphorylation. Interestingly, amyloid-beta-immunotherapy reduces not only amyloid-beta but also tau levels in animal models and in clinical trials. Likewise, it has been shown that tau-immunotherapy also reduces amyloid-beta levels. Thus, even though amyloid-beta immunotherapy is more advanced than tau-immunotherapy, combined amyloid-beta and tau-directed therapies at early stages of the disease have recently been proposed as a strategy to stop the progression of Alzheimer's disease.
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