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A healthy population of mitochondria, maintained by proper fission, fusion, and degradation, is critical for the long-term survival and function of neurons. Here, our discovery of mitophagy intermediates in fission-impaired Drosophila neurons brings new perspective into the relationship between mitochondrial fission and mitophagy. Neurons lacking either the ataxia disease gene Vps13D or the dynamin related protein Drp1 contain enlarged mitochondria that are engaged with autophagy machinery and also lack matrix components. Reporter assays combined with genetic studies imply that mitophagy both initiates and is completed in Drp1 impaired neurons, but fails to complete in Vps13D impaired neurons, which accumulate compromised mitochondria within stalled mito-phagophores. Our findings imply that in fission-defective neurons, mitophagy becomes induced, and that the lipid channel containing protein Vps13D has separable functions in mitochondrial fission and phagophore elongation.

Mutations in the human gene VPS13D cause the adult-onset neurodegenerative disease ataxia. Our previous work showed that disruptions in the Vps13D gene in Drosophila neurons causes mitochondrial defects. However, developmental lethality caused by Vps13D loss limited our understanding of the long-term physiological effects of Vps13D perturbation in neurons. Here, we optimized a previously generated system to temporally knock down Vps13D expression precisely in adult Drosophila neurons using a modification to the Gal4/UAS system. Adult-onset activation of Gal4 was enacted using the chemically-inducible tool which fuses a destabilization-domain to the Gal4 repressor Gal80 (Gal80-DD). Optimization of the Gal80-DD tool shows that feeding animals the DD-stabilizing drug trimethoprim (TMP) during development and rearing at a reduced temperature maximally represses Gal4 activity. Temperature shift and removal of TMP from the food after eclosion robustly activates Gal4 expression in adult neurons. Using the optimized Gal80-DD system, we find that adult-onset Vps13D RNAi expression in neurons causes the accumulation of mitophagy intermediates, progressive deficits in locomotor activity, early lethality, and brain vacuolization characteristic of neurodegeneration. The development of this optimized system allows us to more precisely examine the degenerative phenotypes caused by Vps13D disruption, and can likely be utilized in the future for other genes associated with neurological diseases whose manipulation causes developmental lethality in Drosophila .

Radial glial progenitors (RGPs) in the developing mouse cortex generate excitatory neurons during development. This study examines the role of centriole-related protein Sas4, the mutation of which causes microcephaly in human brain, and shows that centrosome and centriole act to anchor RGPs in the ventricular zone during embryonic neurogenesis. By preventing cell death of RGPs without centrioles, the study also shows that cleavage plane orientation of cell division is not essential for radial glial progenitors' self-renewal. Neuronal production in the mammalian cortex depends on extensive mitoses of radial glial progenitors (RGPs) residing in the ventricular zone (VZ). We examined the function of centrioles in RGPs during cortical neurogenesis in mice by conditional removal of SAS-4, a protein that is required for centriole biogenesis. SAS-4 deletion led to a progressive loss of centrioles, accompanied by RGP detachment from the VZ. Delocalized RGPs did not become outer subventricular zone RGPs (oRGs). Although they remained proliferative, ectopic RGPs, as well as those in the VZ, with a centrosomal deficit exhibited prolonged mitosis, p53 upregulation and apoptosis, resulting in neuronal loss and microcephaly. Simultaneous removal of p53 fully rescued RGP death and microcephaly, but not RGP delocalization and randomized mitotic spindle orientation. Our findings define the functions of centrioles in anchoring RGPs in the VZ and ensuring their efficient mitoses, and reveal the robust adaptability of RGPs in the developing cortex.

Mitochondrial ATP production is a well-known regulator of neuronal excitability. The reciprocal influence of plasma-membrane potential on ATP production, however, remains poorly understood. Here, we describe a mechanism by which depolarized neurons elevate the somatic ATP/ADP ratio in Drosophila glutamatergic neurons. We show that depolarization increased phospholipase-Cβ (PLC-β) activity by promoting the association of the enzyme with its phosphoinositide substrate. Augmented PLC-β activity led to greater release of endoplasmic reticulum Ca2+ via the inositol trisphosphate receptor (IP₃R), increased mitochondrial Ca2+ uptake, and promoted ATP synthesis. Perturbations that decoupled membrane potential from this mode of ATP synthesis led to untrammeled PLC-β–IP₃R activation and a dramatic shortening of Drosophila life-span. Upon investigating the underlying mechanisms, we found that increased sequestration of Ca2+ into endolysosomes was an intermediary in the regulation of lifespan by IP₃Rs. Manipulations that either lowered PLC-β/IP₃R abundance or attenuated endolysosomal Ca2+ overload restored animal longevity. Collectively, our findings demonstrate that depolarization-dependent regulation of PLC-β–IP₃R signaling is required for modulation of the ATP/ADP ratio in healthy glutamatergic neurons, whereas hyperactivation of this axis in chronically depolarized glutamatergic neurons shortens animal lifespan by promoting endolysosomal Ca2+ overload.

We demonstrate that depolarization of Drosophila glutamatergic neurons augmented inositol trisphosphate receptor (IP 3 R)-dependent release of endoplasmic reticulum (ER) Ca 2+ , which in turn potentiated mitochondrial Ca 2+ uptake and ATP production. Perturbations that induced chronic depolarization, including the expression of neurodegeneration-related transgenes, led to the diversion of released ER Ca 2+ into lysosomes and an attendant shortening of animal lifespan. Thus, genetic disruption of PLC-β–IP 3 R signaling or lysosomal Ca 2+ uptake restored longevity in animals with chronically depolarized glutamatergic neurons. Our findings point to aberrant Ca 2+ signaling between the ER and lysosomes as a mechanism by which hyperexcitable glutamatergic neurons shorten animal lifespan. Mitochondrial ATP production is a well-known regulator of neuronal excitability. The reciprocal influence of plasma-membrane potential on ATP production, however, remains poorly understood. Here, we describe a mechanism by which depolarized neurons elevate the somatic ATP/ADP ratio in Drosophila glutamatergic neurons. We show that depolarization increased phospholipase-Cβ (PLC-β) activity by promoting the association of the enzyme with its phosphoinositide substrate. Augmented PLC-β activity led to greater release of endoplasmic reticulum Ca 2+ via the inositol trisphosphate receptor (IP 3 R), increased mitochondrial Ca 2+ uptake, and promoted ATP synthesis. Perturbations that decoupled membrane potential from this mode of ATP synthesis led to untrammeled PLC-β–IP 3 R activation and a dramatic shortening of Drosophila lifespan. Upon investigating the underlying mechanisms, we found that increased sequestration of Ca 2+ into endolysosomes was an intermediary in the regulation of lifespan by IP 3 Rs. Manipulations that either lowered PLC-β/IP 3 R abundance or attenuated endolysosomal Ca 2+ overload restored animal longevity. Collectively, our findings demonstrate that depolarization-dependent regulation of PLC-β–IP 3 R signaling is required for modulation of the ATP/ADP ratio in healthy glutamatergic neurons, whereas hyperactivation of this axis in chronically depolarized glutamatergic neurons shortens animal lifespan by promoting endolysosomal Ca 2+ overload.

The development of the brain relies on the complex coordination of the production of neurons and their long-distance migration to a precise location in the mature brain. Disrupting these processes can cause debilitating disorders of cognitive function. Interestingly, many neuronal developmental disorders are disproportionally associated with mutations in centrosomal genes, highlighting an indispensable role for this cellular organelle in multiple facets of brain development. However, the cell biological foundation of centrosomal regulation of neurogenesis and neuronal migration remains limited. My dissertation work sought to elucidate the various aspects of neocortical development regulated by the centrosome and its associated proteins. In order to investigate the role of the centrosome in neocortical development, we developed a mouse model to remove centrioles from the developing brain through conditional knockout of Sas-4, a microcephaly-associated gene that is required for centriolar duplication. While conditional ablation of Sas-4 in cortical progenitors caused severe microcephaly due to widespread apoptosis, simultaneous removal of apoptosisinitiating factor p53 completely rescued microcephaly. Nevertheless, Sas-4 -/- p53-/- brains displayed phenotypes associated with the loss of centrosomes, including detachment of radial glial progenitors from the ventricular surface, mitotic delay, and randomization of the mitotic cleavage orientation. This data illuminates the function of the centrioles in cortical neurogenesis, and suggests the foremost basis of centrosome-related microcephaly is p53-dependent cell death of progenitor cells. The centrosome is also essential for the proper migration of excitatory cortical neurons. Mutations in the centrosomal gene SDCCAG8 are associated with cognitive defects in humans, yet the mechanism underlying this dysfunction is unknown. I used acute genetic manipulation and classical genetic experiments in mice to show SDCCAG8 is essential for migration of excitatory cortical neurons. SDCCAG8 mediates the recruitment of pericentriolar material via centriolar satellites to ensure the strong microtubule organization at the centrosome necessary for its connection to the nucleus during two-stroke bipolar migration. This work aids in the understanding of the molecular underpinnings associated with the cognitive pathogenesis caused by SDCCAG8 mutations. Taken together, this dissertation emphasize the significance of the centrosome and its associated proteins in various processes regulating cortical development.

Abstract A healthy population of mitochondria, maintained by proper fission, fusion, and degradation, is critical for the long-term survival and function of neurons. Here, our discovery of mitophagy intermediates in fission-impaired Drosophila neurons brings new perspective into the relationship between mitochondrial fission and mitophagy. Neurons lacking either the ataxia disease gene Vps13D or the dynamin related protein Drp1 contain enlarged mitochondria that are engaged with autophagy machinery and also lack matrix components due to rupture. Reporter assays combined with genetic studies imply that mitophagy both initiates and is completed in Drp1 impaired neurons, but fails to complete in Vps13D impaired neurons, which accumulate compromised mitochondria within stalled mito-phagophores. Our findings imply that in fission-defective neurons, mitophagy becomes induced, and that the lipid channel containing protein Vps13D has separable functions in mitochondrial fission and phagophore elongation. Competing Interest Statement The authors have declared no competing interest. Footnotes * This revised manuscript has additional data confirming RNAi phenotypes in mutant animals, quantitative data validating initial results, and additional data using live imaging of an autophagy reporter (Figure 4) to confirm conclusions. Other minor modifications include: a revised title, a re-worded abstract, restructured content (Introduction, Results, Discussion, and Methods), and a revised figure arrangement. The overall conclusions of this revised manuscript remain the same as the original posted manuscript.

Many barriers discourage underrepresented students from pursuing science careers. To access graduate education, undergraduate students must first gain exposure to a particular subject and subsequently accumulate related coursework and research experience. Many underrepresented students lack exposure to developmental biology due to limited undergraduate course offerings and finite resources at smaller institutions. To address this disparity, a group of University of Michigan graduate students and postdoctoral fellows created a portable short course focusing on developmental biology, titled Developing Future Biologists (DFB). This weeklong educational initiative provides hands-on laboratory sessions, interactive lectures, and professional development workshops to teach students about developmental biology and increase awareness of scientific career options. To evaluate course effectiveness, we developed a pre-post assessment, incorporating main ideas from the BioCore Guide. Student understanding of basic concepts and perceived experience in developmental biology increased in DFB participants, despite the abbreviated nature of the course. Here, we provide all course materials and an in-depth analysis of the assessment we created. The DFB portable short course model is an easily adaptable tool that connects undergraduate students with opportunities for advanced study and lowers barriers for underrepresented students in science, technology, engineering, and mathematics.

Background Growing research suggests that food insecurity is associated with worse cognitive functioning; however, longitudinal studies are needed to examine food insecurity and dementia risk. Methods Using data from the 2013‐2021 Panel Study of Income Dynamics, the longest running nationally representative household panel survey, we examined the effects of food insecurity on dementia risk among 3,232 adults (≥65 years). Food insecurity was assessed biennially using the US Household Food Security Survey Module since 2015. Dementia risk was assessed bienially using the Eight Item Interview to Differentiate Aging and Dementia (AD8) since 2017. We used inverse probability weighting and marginal structural models to account for the time‐varying nature of food insecurity and sociodemographic and health confounders. Results In the sample of US households with older adults (mean age (SE), 69.7 (0.2) years, 57% female), the weighted prevalence of food insecurity ranged from 5.3‐7.0% and the weighted prevalence of dementia risk ranged from 20.7‐21.8%. After accounting for baseline and time‐varying confounders, there was a two‐fold association between food insecurity and dementia risk (OR 2.11, 95% CI 1.12, 3.98). In sensitivity analyses, results were similar when expanding the exposure definition to include milder forms of food insecurity, and the outcome definition to include informant‐reported memory loss. Associations were not further modified by sex, race and ethnicity, or household participation in the Supplemental Nutrition Assistance Program. Conclusions Food insecurity is a modifiable social determinant of health. Interventions and policies are needed to reduce food insecurity and promote healthy aging for older adults

Given the recency of the data used and the relevance of race, social class, and gang membership to many substantive topics, this book will be useful for researchers in sociology, criminology, or criminal justice.