6 research outputs found
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Activity-dependent trafficking of lysosomes in dendrites and dendritic spines.
In neurons, lysosomes, which degrade membrane and cytoplasmic components, are thought to primarily reside in somatic and axonal compartments, but there is little understanding of their distribution and function in dendrites. Here, we used conventional and two-photon imaging and electron microscopy to show that lysosomes traffic bidirectionally in dendrites and are present in dendritic spines. We find that lysosome inhibition alters their mobility and also decreases dendritic spine number. Furthermore, perturbing microtubule and actin cytoskeletal dynamics has an inverse relationship on the distribution and motility of lysosomes in dendrites. We also find trafficking of lysosomes is correlated with synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors. Strikingly, lysosomes traffic to dendritic spines in an activity-dependent manner and can be recruited to individual spines in response to local activation. These data indicate the position of lysosomes is regulated by synaptic activity and thus plays an instructive role in the turnover of synaptic membrane proteins
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Characterization of Activity-Dependent Trafficking and Distribution of Lysosomes in Neurons
My dissertation research focused on studying activity-dependent protein degradation in neurons primarily focusing on lysosomes, a degradative organelle. The role of lysosomes in regulating neuronal activity has been virtually unexplored, but their presence in dendrites was recently confirmed. My thesis work served to try to understand their role in dendrites, showing that lysosomes can be recruited to spines and their inhibition causes mEPSP frequency to decrease. I then expanded on this work to characterize their distribution throughout the entire dendrite, demonstrating that long term depression (LTD) and long term potentiation (LTP) cause lysosomes to shift proximally and distally respectively. This shift is associated with a decrease in surface GluA1 AMPA receptor subunits, suggesting that lysosomes may play a role in regulating the local intensity of LTP and LTD.In Chapter IV, I focus on AMPA receptor half-life by evaluating the effect of the phosphorylation state of serine 845 (s845). This phosphor-site has been shown to regulate internalization of GluA1. I found that phosphorylation of this site increases when neuronal activity is upregulated via bicuculline treatment, and that this phosphorylation changes over time, peaking between 4-8 hours. Inhibiting protein kinase A in conjunction with this treatment causes a synthesis-dependent degradation of GluA1.
Chapter V describes the development of a method to purify lysosomes from neurons in preparation for proteomic analysis via mass spectrometry. This method was adapted to neurons from an existing method to purify lysosomes in dividing cells and shown to have the sensitivity to detect autophagy-induced changes in the lysosomal proteome
Recommended from our members
Characterization of Activity-Dependent Trafficking and Distribution of Lysosomes in Neurons
My dissertation research focused on studying activity-dependent protein degradation in neurons primarily focusing on lysosomes, a degradative organelle. The role of lysosomes in regulating neuronal activity has been virtually unexplored, but their presence in dendrites was recently confirmed. My thesis work served to try to understand their role in dendrites, showing that lysosomes can be recruited to spines and their inhibition causes mEPSP frequency to decrease. I then expanded on this work to characterize their distribution throughout the entire dendrite, demonstrating that long term depression (LTD) and long term potentiation (LTP) cause lysosomes to shift proximally and distally respectively. This shift is associated with a decrease in surface GluA1 AMPA receptor subunits, suggesting that lysosomes may play a role in regulating the local intensity of LTP and LTD.In Chapter IV, I focus on AMPA receptor half-life by evaluating the effect of the phosphorylation state of serine 845 (s845). This phosphor-site has been shown to regulate internalization of GluA1. I found that phosphorylation of this site increases when neuronal activity is upregulated via bicuculline treatment, and that this phosphorylation changes over time, peaking between 4-8 hours. Inhibiting protein kinase A in conjunction with this treatment causes a synthesis-dependent degradation of GluA1.
Chapter V describes the development of a method to purify lysosomes from neurons in preparation for proteomic analysis via mass spectrometry. This method was adapted to neurons from an existing method to purify lysosomes in dividing cells and shown to have the sensitivity to detect autophagy-induced changes in the lysosomal proteome
Recommended from our members
Activity-dependent trafficking of lysosomes in dendrites and dendritic spines.
In neurons, lysosomes, which degrade membrane and cytoplasmic components, are thought to primarily reside in somatic and axonal compartments, but there is little understanding of their distribution and function in dendrites. Here, we used conventional and two-photon imaging and electron microscopy to show that lysosomes traffic bidirectionally in dendrites and are present in dendritic spines. We find that lysosome inhibition alters their mobility and also decreases dendritic spine number. Furthermore, perturbing microtubule and actin cytoskeletal dynamics has an inverse relationship on the distribution and motility of lysosomes in dendrites. We also find trafficking of lysosomes is correlated with synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors. Strikingly, lysosomes traffic to dendritic spines in an activity-dependent manner and can be recruited to individual spines in response to local activation. These data indicate the position of lysosomes is regulated by synaptic activity and thus plays an instructive role in the turnover of synaptic membrane proteins
Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021
BackgroundEstimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period.Methods22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution.FindingsGlobal all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations.InterpretationGlobal adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic