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Author

Dan Lindholm

Other affiliations: University of Melbourne, Max Planck Society, Harvard University  ...read more
Bio: Dan Lindholm is an academic researcher from Minerva Foundation Institute for Medical Research. The author has contributed to research in topics: Nerve growth factor & Neurotrophic factors. The author has an hindex of 70, co-authored 235 publications receiving 23924 citations. Previous affiliations of Dan Lindholm include University of Melbourne & Max Planck Society.


Papers
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Journal ArticleDOI
Daniel J. Klionsky1, Kotb Abdelmohsen2, Akihisa Abe3, Joynal Abedin4  +2519 moreInstitutions (695)
TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

5,187 citations

Journal ArticleDOI
01 Jan 1987-Nature
TL;DR: It is demonstrated that the effect of macrophages on NGF-mRNA levels in cultured explants of sciatic nerve can be mimicked by conditioned media of activated macrophage, and that interleukin-1 is the responsible agent.
Abstract: The Schwann cells and fibroblast-like cells of the intact sciatic nerve of adult rats synthesize very little nerve growth factor (NGF) (ref. 1). After lesion, however, there is a dramatic increase in the amounts of both NGF-mRNA and NGF protein synthesized by the sciatic non-neuronal cells1,2. This local increase in NGF synthesis partially replaces the interrupted NGF supply from the periphery to the NGF-responsive sensory and sympathetic neurons, whose axons run within the sciatic nerve1. Macrophages, known to invade the site of nerve lesion during wallerian degeneration3,4, are important in the regulation of NGF synthesis5. Here we demonstrate that the effect of macrophages on NGF-mRNA levels in cultured explants of sciatic nerve can be mimicked by conditioned media of activated macrophages, and that interleukin-1 is the responsible agent.

996 citations

Journal ArticleDOI
TL;DR: The results suggest that the synthesis of these two neurotrophic factors in the brain is regulated by neuronal activity via non‐NMDA glutamate receptors.
Abstract: The mRNAs of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) exhibit a similar, though not identical, regional and cellular distribution in the rodent brain. In situ hybridization experiments have shown that BDNF, like NGF, is predominantly expressed by neurons. The neuronal localization of the mRNAs of these two neurotrophic molecules raised the question as to whether neuronal activity might be involved in the regulation of their synthesis. After we had demonstrated that depolarization with high potassium (50 mM) resulted in an increase in the levels of both BDNF and NGF mRNAs in cultures of hippocampal neurons, we investigated the effect of a large number of transmitter substances. Kainic acid, a glutamate receptor agonist, was by far the most effective in increasing BDNF and NGF mRNA levels in the neurons, but neither N-methyl-D-aspartic acid (NMDA) nor inhibitors of the NMDA glutamate receptors had any effect. However, the kainic acid mediated increase was blocked by antagonists of non-NMDA receptors. Kainic acid also elevated levels of BDNF and NGF mRNAs in rat hippocampus and cortex in vivo. These results suggest that the synthesis of these two neurotrophic factors in the brain is regulated by neuronal activity via non-NMDA glutamate receptors.

900 citations

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TL;DR: The possible role of ER stress in neurodegenerative diseases is discussed, and current knowledge in this field that may reveal novel insight into disease mechanisms and help to design better therapies for these disorders are highlighted.
Abstract: Endoplasmic reticulum (ER) stress is caused by disturbances in the structure and function of the ER with the accumulation of misfolded proteins and alterations in the calcium homeostasis. The ER response is characterized by changes in specific proteins, causing translational attenuation, induction of ER chaperones and degradation of misfolded proteins. In case of prolonged or aggravated ER stress, cellular signals leading to cell death are activated. ER stress has been suggested to be involved in some human neuronal diseases, such as Parkinson's disease, Alzheimer's and prion disease, as well as other disorders. The exact contributions to and casual effects of ER stress in the various disease processes, however, are not known. Here we will discuss the possible role of ER stress in neurodegenerative diseases, and highlight current knowledge in this field that may reveal novel insight into disease mechanisms and help to design better therapies for these disorders.

812 citations

Journal ArticleDOI
TL;DR: Taniuchi et al. as discussed by the authors found that the levels of nerve growth factor (NGF) mRNA (mRNANGF) and NGF receptor mRNA(mRNA(rec)) in the sciatic nerve were 10 and 120 times higher, respectively, than in adult animals.
Abstract: In newborn rats the levels of nerve growth factor (NGF) mRNA (mRNANGF) and NGF receptor mRNA (mRNA(rec)) in the sciatic nerve were 10 and 120 times higher, respectively, than in adult animals. mRNA(rec) levels decreased steadily from birth, approaching adult levels by the third postnatal week, whereas mRNANGF levels decreased only after the first postnatal week, although also reaching adult levels by the third week. Transection of the adult sciatic nerve resulted in a marked biphasic increase in mRNANGF with time. On the proximal side of the cut, this increase was confined to the area immediately adjacent to the cut; peripherally, a similar biphasic increase was present in all segments. mRNA(rec) levels were also markedly elevated distal to the transection site, in agreement with previous results obtained by immunological methods [Taniuchi, M., Clark, H. B. & Johnson, E. M., Jr. (1986) Proc. Natl. Acad. Sci. USA 83, 4094-4098]. Following a crush lesion (allowing regeneration), the mRNA(rec) levels were rapidly down-regulated as the regenerating nerve fibers passed through the distal segments. Down-regulation of mRNANGF also occurred during regeneration but was slower and not as extensive as that of mRNA(rec) over the time period studied. Changes in mRNANGF and mRNA(rec) occurring in vivo after transection were compared with those observed in pieces of sciatic nerve kept in culture. No difference was found for mRNA(rec). Only the initial rapid increase in mRNANGF occurred in culture, but the in vivo situation could be mimicked by the addition of activated macrophages. This reflects the situation in vivo where, after nerve lesion, macrophages infiltrate the area of the Wallerian degeneration. These results suggest that mRNANGF synthesis in sciatic non-neuronal cells is regulated by macrophages, whereas mRNA(rec) synthesis is determined by axonal contact.

722 citations


Cited by
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01 Jan 2020
TL;DR: Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.
Abstract: Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

4,408 citations

Journal ArticleDOI
TL;DR: An understanding of intercellular signalling pathways for microglia proliferation and activation could form a rational basis for targeted intervention on glial reactions to injuries in the CNS.

4,372 citations

Journal ArticleDOI
TL;DR: Authors/Task Force Members: Franz-Josef Neumann* (ESC Chairperson) (Germany), Miguel Sousa-Uva* (EACTS Chair person) (Portugal), Anders Ahlsson (Sweden), Fernando Alfonso (Spain), Adrian P. Banning (UK), Umberto Benedetto (UK).

4,342 citations

Journal ArticleDOI
TL;DR: By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.

4,319 citations

Journal ArticleDOI
TL;DR: Neurotrophins regulate development, maintenance, and function of vertebrate nervous systems, and control synaptic function and synaptic plasticity, while continuing to modulate neuronal survival.
Abstract: Neurotrophins regulate development, maintenance, and function of vertebrate nervous systems. Neurotrophins activate two different classes of receptors, the Trk family of receptor tyrosine kinases and p75NTR, a member of the TNF receptor superfamily. Through these, neurotrophins activate many signaling pathways, including those mediated by ras and members of the cdc-42/ras/rho G protein families, and the MAP kinase, PI-3 kinase, and Jun kinase cascades. During development, limiting amounts of neurotrophins function as survival factors to ensure a match between the number of surviving neurons and the requirement for appropriate target innervation. They also regulate cell fate decisions, axon growth, dendrite pruning, the patterning of innervation and the expression of proteins crucial for normal neuronal function, such as neurotransmitters and ion channels. These proteins also regulate many aspects of neural function. In the mature nervous system, they control synaptic function and synaptic plasticity, while continuing to modulate neuronal survival.

3,968 citations