Astrocytic Dynamin-Like Protein 1 Regulates Neuronal Protection against Excitotoxicity in Parkinson Disease

Mitochondrial dynamics has recently become an area of piqued interest in neurodegenerative disorders, including Parkinson disease (PD); however, the contribution of astrocytes to these disorders remains unclear. Here, we show that the level of dynamin-like protein 1 (Dlp1; official name DNM1L), which promotes mitochondrial fission, is lower in astrocytes from the brains of PD patients, and that decreased astrocytic Dlp1 likely represents a relatively early event in PD pathogenesis. In support of this conclusion, we show that Dlp1 knockdown dramatically affects mitochondrial morphological characteristics and localization in astrocytes, impairs the ability of astrocytes to adequately protect neurons from the excitotoxic effects of glutamate, and increases intracellular Ca²⁺ in response to extracellular glutamate, resulting from compromised intracellular Ca²⁺ buffering. Taken together, our results suggest that astrocytic mitochondrial Dlp1 is a key protein in mitochondrial dynamics and decreased Dlp1 may interfere with neuron survival in PD by disrupting Ca²⁺-coupled glutamate uptake.Parkinson disease (PD) is a neurodegenerative disorder clinically characterized by both motor and nonmotor symptoms.^1–3 The loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) is the primary cause of the motor deficits,⁴ whereas nonmotor symptoms are the result of dysfunction in multiple brain regions.^2,3 Until recently, most investigations have focused on the neuronal pathogenesis. However, accumulating evidence shows that astrocytes, which have multiple neuroprotective roles,^5,6 contribute to neuronal loss in PD.⁷Decreased respiratory chain activity⁸ and increased oxidative damage in the SNpc^9,10 contribute to neuronal demise in PD. Among proteins that regulate mitochondrial functions,¹¹ those that regulate mitochondrial fission [dynamin-like protein 1 (Dlp1; official name DNM1L), fission 1], and fusion [(mitofusins 1 and 2 and optic atrophy 1)] are particularly interesting. Models of PD show dramatic effects in mitochondrial morphological features, which can be rescued by altering expression of these proteins.^12,13 Our previous study profiled the mitochondrial fraction of the SNpc in healthy control and PD patients and identified specific alterations in expression of Dlp1, but not other mitochondrial fission and fusion proteins in PD brains,¹⁴ suggesting Dlp1 plays a role in PD pathogenesis. However, the cellular origin and consequences of decreased Dlp1 expression remain to be fully elucidated.A recent investigation found that Dlp1 potentially interacts with the glutamate transporter 1 (GLT-1; official name SLC1A2),¹⁵ which is specifically expressed by astrocytes,¹⁶ implicating this cell type in Dlp1-mediated pathogenic effects. In theory, disrupting astrocyte regulation of extracellular glutamate [also a function of the glutamate aspartate transporter (GLAST; official name SLC1A3¹⁷)] could result in excessive extracellular glutamate. This excess glutamate could prolong the opening of neuronal N-methyl-d-aspartate (NMDA) receptors,¹⁸ resulting in excessive Ca²⁺ entry and, ultimately, neuronal death. Indeed, this phenomenon of excitotoxicity has been implicated in PD and animal models of PD,^19,20 as well as in other neurodegenerative diseases.To test the hypothesis that decreased astrocytic Dlp1 expression contributes to neurodegeneration in PD, we measured astrocytic and neuronal Dlp1 expression, in the SNpc and cortex, in both PD and healthy control patients and explored the molecular mechanisms related to astrocytic dysfunction resulting from decreased Dlp1 expression.     

Cross-evaluation of metrics to estimate the significance of creative works

In a world overflowing with creative works, it is useful to be able to filter out the unimportant works so that the significant ones can be identified and thereby absorbed. An automated method could provide an objective approach for evaluating the significance of works on a universal scale. However, there have been few attempts at creating such a measure, and there are few “ground truths” for validating the effectiveness of potential metrics for significance. For movies, the US Library of Congress’s National Film Registry (NFR) contains American films that are “culturally, historically, or aesthetically significant” as chosen through a careful evaluation and deliberation process. By analyzing a network of citations between 15,425 United States-produced films procured from the Internet Movie Database (IMDb), we obtain several automated metrics for significance. The best of these metrics is able to indicate a film’s presence in the NFR at least as well or better than metrics based on aggregated expert opinions or large population surveys. Importantly, automated metrics can easily be applied to older films for which no other rating may be available. Our results may have implications for the evaluation of other creative works such as scientific research.For many types of creative works—including films, novels, plays, poems, paintings, and scientific research—there are important efforts for identifying which creations are of the highest quality and to honor their creators, including the Oscars, the Pulitzer Prize, and the Nobel. Unfortunately, these distinctions recognize only a small number of creators and sometimes generate more controversy than consensus. The reason is that one of the challenges associated with measuring the intrinsic quality of a creative work is how to formally define “quality.”In statistical modeling, this problem is typically addressed by positing the existence of latent (hidden) variables, which are unmeasurable but can be inferred from the values of other, measurable variables (1). For creative works, we presume there exists a latent variable, which we call “significance.” Significance can be thought of as the lasting importance of a creative work. Significant works stand the test of time through novel ideas or breakthrough discoveries that change the landscape of a field or culture. Under this perspective, what is usually called “quality” is not the actual value of the latent variable, but an individual’s or group’s estimation of that value. Not surprisingly, the subjective evaluation of the unmeasurable true significance of the work is controversial, dependent on the historical moment, and very much “in the eye of the beholder.”Alternative methods for estimating the significance of a creative work fall under the labels of “impact” and “influence.” Impact may be defined as the overall effect of a creative work on an individual, industry, or society at large, and it can be measured as sales, downloads, media mentions, or other possible means. However, in many cases, impact may be a poor proxy for significance. For example, Duck Soup (2) is generally considered to be the Marx Brothers’ greatest film, but it was a financial disappointment for Paramount Pictures in 1933 (3). Influence may be defined as the extent to which a creative work is a source of inspiration for later works. Although this perspective provides a more nuanced estimation of significance, it is also more difficult to measure. For example, Ingmar Bergman’s influence on later film directors is undebatable (4, 5), but not easily quantified. Despite different strengths and limitations, any quantitative approaches that result in an adequate estimation of significance should be strongly correlated when evaluated over a large corpus of creative works.By definition, the latent variable for a creative work is inaccessible. However, for the medium of films—which will be the focus of this work—there is in fact as close to a measurement of the latent variable as one could hope for. In 1988, the US Government established the US National Film Preservation Board (NFPB) as part of the Library of Congress (6). The NFPB is tasked with selecting films deemed “culturally, historically, or aesthetically significant” for preservation in the National Film Registry (NFR). The NFR currently comprises 625 films “of enduring importance to American culture” (7). The careful evaluation and deliberation involved in the selection process each year, and the requirement of films being at least 10 y old to be eligible for induction, demonstrates the NFPB’s true commitment to identifying films of significance.Presence in the NFR is a binary variable as no distinctions are made between inducted films. This means that, although it can function as a “ground truth” for significances above a threshold value, it cannot discern the comparative significance of films. One of the goals of this study is to determine whether there are metrics that can accurately estimate film significance over a range of numerical values and for a large number of films. To this end, we investigate proxies of film quality, impact, or influence as potential measures of significance.One can identify three main classes of approaches for estimating the significance of films: expert opinions, wisdom of the crowd, and automated methods. Expert opinions tend to measure the subjective quality of a film, whereas wisdom-of-the-crowd approaches tend to produce metrics that measure impact or popularity through broad-based surveys. Ideally, we can obtain an automated method that can measure influence. However, the best-known automated methods for films pertain to economic impact, such as the opening weekend or total box office gross. More recently, researchers and film industry professionals have evaluated films using electronic measures, such as Twitter mentions (8) and frequency of Wikipedia edits (9), but these may also be better indicators of impact or popularity. For an automated, objective measure that pertains to a film’s influence, we turn to scientific works for an appropriate analog.The network formed by citations from scientific literature is at the center of much research (10–12). Although some of the research on the scientific citation network aims to answer questions on citations between academic fields (13) or sex bias in academia (14), much work seeks to determine who is “winning” at science (15). Researchers have identified numerous metrics that are said to determine which paper (16), researcher (17), or journal (18) is the best, most significant, or most influential. These metrics range from the simple, such as total number of citations (19), to the complex, such as PageRank (20). The scientific citation network provides large quantities of data to analyze and dissect (12, 15, 21). If it were not for the expectation that researchers cite relevant literature, these metrics and indeed this avenue of study would not exist.Like scientists, artists are often influenced or inspired by prior works. However, unlike researchers, artists are typically not obligated to cite the influences on their work. If data identifying citations between creative works could be made or obtained, we then could apply citation-based analyses to develop an objective metric for estimating the significance of a given work. As it happens, such data now exists. The Internet Movie Database (IMDb) (www.imdb.com) holds the largest digital collection of metadata on films, television programs, and other visual media. For each film listed in IMDb, there are multiple sections, from information about the cast and crew to critic reviews and notable quotes. Nestled among the deluge of metadata for each film is a section titled “connections,” which contains a list of references and links to and from other films (Fig. 1). By analyzing this citation network obtained from user-edited data, we can investigate the suitability of metrics to estimate film significance based on the spread of influence in the world of motion pictures.Open in a separate windowFig. 1.Subgraph of film connections network. Films are ordered chronologically, based on year of release, from bottom to top (not to scale). A connection between two films exists if a sequence, sentence, character, or other part of the referenced film has been adopted, used, or imitated in the referencing film. For example, there is a connection from 1987’s Raising Arizona (22) to 1981’s The Evil Dead (23) because the main characters of both films drive an Oldsmobile Delta 88. Values represent the time lag of the connection, measured in years.     

From the Cover: Strong upslope shifts in Chimborazo's vegetation over two centuries since Humboldt

Global climate change is driving species poleward and upward in high-latitude regions, but the extent to which the biodiverse tropics are similarly affected is poorly known due to a scarcity of historical records. In 1802, Alexander von Humboldt ascended the Chimborazo volcano in Ecuador. He recorded the distribution of plant species and vegetation zones along its slopes and in surrounding parts of the Andes. We revisited Chimborazo in 2012, precisely 210 y after Humboldt’s expedition. We documented upward shifts in the distribution of vegetation zones as well as increases in maximum elevation limits of individual plant taxa of >500 m on average. These range shifts are consistent with increased temperatures and glacier retreat on Chimborazo since Humboldt’s study. Our findings provide evidence that global warming is strongly reshaping tropical plant distributions, consistent with Humboldt’s proposal that climate is the primary control on the altitudinal distribution of vegetation.The biological impacts of ongoing climate change (1) are already apparent in species’ poleward and upslope range shifts and earlier spring events (2–9). However, most studies stem from high-latitude areas and are generally restricted to dynamics across the past few decades (10). To our knowledge, only three previous resurveys have studied range shifts of tropical plant taxa, all at <4,000 m in elevation (7, 8, 11). Modeling (12) and paleoecological studies (13) suggest that tropical montane vegetation should be highly sensitive to climate change. However, researchers strongly debate whether tropical plants are tracking warming temperatures along elevation gradients, with most (although scarce) studies indicating they are lagging behind (cf. 14, 15). Such lags could have negative effects on the distributions of species dependent on certain plant taxa, e.g., as a food source (16). The question is particularly urgent given the growing evidence of systematically stronger warming rates in high-mountain environments (17).The legacy and works of Alexander von Humboldt (1769–1859) not only constitute the foundation of biogeography, but also what is likely the oldest dataset on altitudinal ranges of plant species. The observations recorded by Humboldt and Aimé Bonpland (1773–1858) during their travels in Central and South America, and synthesized in a Tableau of Mt. Chimborazo (summit 6,268 m above sea level) and accompanying essay (18), provide a unique opportunity to study tropical vegetation changes over a period of 210 y. To our knowledge, this period is more than twice as long as any previous resurvey study based on historical biodiversity records (11, 19). We revisited the upper slopes of the Chimborazo volcano in June 2012. Our aim was to record the current elevational distribution of plants and test for upward shifts since Humboldt’s expedition, as a response to anthropogenic global warming. We sampled plant species presence and abundance along transects every 100 m of elevation between 3,800 and 5,200 m. Three main findings, comparing our surveys to Humboldt’s data, support strong upward shifts of plant distributions: a higher upper limit for plant growth, increased elevation of vegetation zones, and upward shifts in the upper range limits of most individual taxa.