Timothy Sargeant

Timothy Sargeant
South Australian Health and Medical Research Institute | SAHMRI · Lysosomal Health in Ageing

PhD
Group Leader of Lysosomal Health in Ageing, SAHMRI - Delay the onset of dementia using the lysosomal system

About

59
Publications
12,779
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1,353
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Introduction
Tim currently works at the Hopwood Centre for Neurobiology, South Australian Health and Medical Research Institute. Tim does research in Molecular Biology, Neuroscience and Cell Biology. Find me on twitter - @TimSargeant1
Additional affiliations
June 2012 - December 2014
University of Cambridge
Position
  • PostDoc Position
April 2008 - June 2012
University of Cambridge
Position
  • PostDoc Position
February 2005 - February 2008
Victoria University of Wellington
Position
  • PhD Student

Publications

Publications (59)
Preprint
Autophagy is an intracellular recycling process that degrades harmful molecules, maintains optimal composition of cellular organelles and enables survival during starvation. Previous studies have demonstrated how transcription factors (TFs) can increase autophagy with therapeutic potential (impaired autophagy in the ageing brain, in particular, may...
Article
Background Intermittent fasting (IF) activates autophagy in cardiac muscle and pancreatic islets. We examined the effect of IF on markers of autophagy in liver and skeletal muscle in mice and in humans. Methods Ten-week-old C57BL/6J male mice were ad-libitum fed a high-fat (HFD) or chow diet for 8 weeks, before randomisation to AL or IF (24h fast,...
Article
Full-text available
Lysosomal network abnormalities are an increasingly recognised feature of Alzheimer’s disease (AD), which appear early and are progressive in nature. Sandhoff disease and Tay-Sachs disease (neurological lysosomal storage diseases caused by mutations in genes that code for critical subunits of β-hexosaminidase) result in accumulation of amyloid-β (A...
Article
Full-text available
The gut microbiome-brain axis exerts considerable influence on the development and regulation of the central nervous system. Numerous pathways have been identified by which the gut microbiome communicates with the brain, falling largely into the two broad categories of neuronal innervation and immune-mediated mechanisms. We describe an additional r...
Article
Full-text available
Age‐related diseases represent some of largest unmet clinical needs of our time. While treatment of specific disease‐related signs has had some success (for example the effect of statin drugs on slowing progression of atherosclerosis), slowing biological ageing itself represents a target that could significantly increase health‐span and reduce the...
Article
Full-text available
The ATG8 family of proteins regulates autophagy in a variety of ways. Recently, ATG8s were demonstrated to conjugate directly to cellular proteins in a process termed “ATG8ylation,” which is amplified by mitochondrial damage and antagonized by ATG4 proteases. ATG8s may have an emerging role as small protein modifiers.
Article
Preclinical research shows that autophagy is a modifiable process that holds promise for preventing human age-related disease. However, this knowledge has not been clinically translated. Here, we discuss recent developments in the ability to measure human autophagy, and why it is a critical step for translation.
Article
Degradation and clearance of cellular waste in the autophagic and endo-lysosomal systems is important for normal physiology and prevention of common late-onset diseases such as Alzheimer's disease (AD). Phosphatidylinostol-binding clathrin assembly protein (PICALM) is a robust AD risk factor gene and encodes an endosomal protein clathrin-binding cy...
Article
Full-text available
Studies investigating whether there is a causative link between the gut microbiota and lifespan have largely been restricted to invertebrates or to mice with a reduced lifespan because of a genetic deficiency. We investigate the effect of early-life antibiotic exposure on otherwise healthy, normal chow-fed, wild-type mice, monitoring these mice for...
Article
Full-text available
The mechanistic target of rapamycin complex 1 (mTORC1) is an important regulator of cellular metabolism that is commonly hyperactivated in cancer. Recent cancer genome screens have identified multiple mutations in Ras-homolog enriched in brain (Rheb), the primary activator of mTORC1 that might act as driver oncogenes by causing hyperactivation of m...
Article
Autophagy is a catabolic process that collects and degrades damaged or unwanted cellular materials such as protein aggregates. Defective brain autophagy has been linked to diseases such as Alzheimer’s disease. Autophagy is regulated by the protein kinase mTOR (mechanistic target of rapamycin). Although already demonstrated in vitro, it remains cont...
Article
Full-text available
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...
Article
Tauopathies define a broad range of neurodegenerative diseases that encompass pathological aggregation of the microtubule-associated protein tau. Although tau aggregation is a central feature of these diseases, their underlying pathobiology is remarkably heterogeneous at the molecular level. In this review, we summarize critical differences that ac...
Article
Measurement of autophagic flux in vivo is critical to understand how autophagy can be used to combat disease. Neurodegenerative diseases have a special relationship with autophagy, which makes measurement of autophagy in the brain a significant research priority. Currently, measurement of autophagic flux is possible through use of transgenic constr...
Article
Autophagic flux is a critical cellular process that is vastly under-appreciated in terms of its importance to human health. Preclinical studies have demonstrated that reductions in autophagic flux cause cancer and exacerbate chronic diseases, including heart disease and the pathological hallmarks of dementia. Autophagic flux can be increased by tar...
Article
The macroautophagy/autophagy-lysosome axis enables the clearance and degradation of cytoplasmic components including protein aggregates, damaged organelles and invading pathogens. Protein aggregation and lysosomal system dysfunction in the brain are common features of several late-onset neurological disorders including Alzheimer disease. Spatial ov...
Preprint
The mechanistic target of rapamycin complex 1 (mTORC1) is an important regulator of cellular metabolism that is commonly hyperactivated in cancer. Recent cancer genome screens have identified multiple mutations in Ras-homolog enriched in brain (Rheb), the primary activator of mTORC1, that might act as driver oncogenes by causing hyperactivation of...
Article
Lysosomal network dysfunction is a prominent feature of Alzheimer’s disease. Although transgenic mouse models of Alzheimer’s disease are known to model some aspects of lysosomal network dysfunction, the lysosomal network has not yet been examined in the knock-in AppNL-G-F/NL-G-F mouse. We aimed to determine whether AppNL-G-F/NL-G-F mice exhibit dis...
Article
The enrichment of lysosomes is a useful way to study their structure and function. These dynamic vesicles can be enriched from cell cultures in a variety of ways including immunoprecipitation and fluorescence-activated organelle sorting. These methods are extremely precise but often require the transfection and expression of an affinity or fluoroph...
Article
Full-text available
Amyloids are fibrous proteins aggregated into toxic forms that are implicated in several chronic disorders. More than 30 diseases show deposition of fibrous amyloid proteins associated with cell loss and degeneration in the affected tissues. Evidence demonstrates that amyloid diseases result from protein aggregation or impaired amyloid clearance, b...
Article
Numerous studies have reported that inhibition of MTOR (mechanistic target of rapamycin kinase) clearly reduces Alzheimer disease neuropathological hallmarks in mouse models. This has resulted in calls for the use of the MTOR inhibitor rapamycin for the treatment of dementia in humans. Unfortunately, intervention with rapamycin in these mouse studi...
Article
Full-text available
Retromer is a peripheral membrane protein complex that coordinates multiple vesicular trafficking events within the endolysosomal system. Here, we demonstrate that retromer is required for the maintenance of normal lysosomal morphology and function. The knockout of retromer subunit Vps35 causes an ultrastructural alteration in lysosomal structure a...
Article
Late-onset Alzheimer's disease is the most common dementia type, yet no treatment exists to stop the neurodegeneration. Evidence from monogenic lysosomal diseases, neuronal pathology and experimental models suggest that autophagic and endolysosomal dysfunction may contribute to neurodegeneration by disrupting the degradation of potentially neurotox...
Article
Lysosomal vesicles around neuritic plaques are thought to drive Alzheimer's disease by providing ideal microenvironments for generation of amyloid‐β. Although lysosomal vesicles are present at every amyloid plaque in mouse models of Alzheimer's disease, the number of amyloid plaques that contain lysosomal vesicles in the human brain remains unknown...
Article
Full-text available
Lysosome function is essential in cellular homeostasis. In addition to its recycling role, the lysosome has recently been recognised as a cellular signalling hub. We have shown in mammary epithelial cells, both in vivo and in vitro, that signal transducer and activator of transcription 3 (Stat3) modulates lysosome biogenesis and can promote the rel...
Article
Lysosome function is essential in cellular homeostasis. In addition to its recycling role, the lysosome has recently been recognised as a cellular signalling hub. We have shown in mammary epithelial cells, both in vivo and in vitro, that signal transducer and activator of transcription 3 (Stat3) modulates lysosome biogenesis and can promote the rel...
Article
The recent development of knock-in mouse models of Alzheimer's disease provides distinct advantages over traditional transgenic mouse models that rely on over-expression of amyloid precursor protein. Two such knock-in models that have recently been widely adopted by Alzheimer's researchers are the App(NL-F) and App(NL-G-F) mice. This study aimed to...
Chapter
Involution of the mammary gland occurs at the end of every period of lactation and is an essential process to return the gland to a pre-pregnant state in readiness for the next pregnancy. Involution is a complex process of regulated alveolar cell death coupled with tissue remodeling and requires exquisite control of transcription and signaling. The...
Article
Alzheimer's disease is the most important cause of dementia but there is no therapy that has been demonstrated to stop or slow disease progression. Amyloid precursor protein (APP) is the source of amyloid-β (Aβ), which aggregates in Alzheimer's disease to form toxic oligomeric species. The endo-lysosomal system can clear APP and Aβ from the cell if...
Article
Full-text available
Alzheimer's disease (AD) is the most common cause of dementia and its prevalence will increase significantly in the coming decades. Although important progress has been made, fundamental pathogenic mechanisms as well as most hereditary contributions to the sporadic form of the disease remain unknown. In this review, we examine the now substantial l...
Article
Full-text available
A commentary on Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice by Tanaka, Y., Chambers, J. K., Matsuwaki, T., Yamanouchi, K., and Nishihara, M. (2014). Acta Neuropathol. Commun. 2, 78. doi: 10.1186/s40478-014-0078-x The recent paper by Tanaka and colleagues details the neuropa...
Article
Full-text available
The exact mechanism of secretion of the milk fat globule (MFG) from the mammary secretory cell is still controversial. We have previously suggested close involvement of Golgi vesicles in this process. This paper provides direct immunocytochemical evidence that butyrophilin is present in the Golgi stack and vesicles in ovine and caprine mammary glan...
Article
Full-text available
We have previously demonstrated that Stat3 regulates lysosomal-mediated programmed cell death (LM-PCD) during mouse mammary gland involution in vivo. However, the mechanism that controls the release of lysosomal cathepsins to initiate cell death in this context has not been elucidated. We show here that Stat3 regulates the formation of large lysoso...
Article
Mammary gland involution involves a process that includes one of the most dramatic examples of cell death in an adult mammalian organism. We have previously shown that Stat3 regulates a lysosomal pathway of cell death in the first 48 hours of involution and induces lysosome leakiness in mammary epithelial cells. Interestingly, Stat3 is associated a...
Article
Full-text available
Involution is a process whereby the mammary gland undergoes extensive tissue remodelling involving exquisitely coordinated cell death, extracellular matrix degradation and adipose tissue regeneration following the weaning of offspring. These processes are mediated in part through Jak/Stat signalling pathways, which can be deregulated in breast canc...
Article
TNF, signaling through TNFR2, has been implicated in tissue repair, a process that in the heart may be mediated by activated resident cardiac stem cells (CSCs). The objective of our study is to determine whether ligation of TNFR2 can induce activation of resident CSCs in the setting of ischemic cardiac injury. We show that in human cardiac tissue a...
Data
Storage of glycoconjugate shown by PAS staining in Hexb−/−HexTg and Hexb−/−SYNTg brain at humane endpoint. − = no PAS staining, +++ = strong/widespread PAS staining similar to Hexb−/− mouse at humane endpoint. (DOC)
Data
Hexb+/− mouse, six months of age. (WMV)
Data
Hexb−/−HexTg mouse (−dox), six months of age. (WMV)
Data
In situ hybridization showing tet-transactivator mRNA in the brain and staining for β-hexosaminidase activity. Staining for tet-transactivator transcript (purple NBT/BCIP staining) correlated with staining for transgenic β-hexosaminidase activity (red), except for the olfactory bulbs of the Hexb−/−SYNTg mouse, where transcript could not be found in...
Data
Hexb−/−HexTg mouse (−dox), one year of age. (WMV)
Data
Hexb−/−HexTg mouse fed doxycycline starting at five weeks of age, viewed at humane endpoint of approximately six months of age. (WMV)
Data
In vitro validation of inducible expression constructs. To determine whether cassettes would express Hexb coding sequence, HEK 293T cells were transiently transfected using the calcium phosphate method and six micrograms of plasmid DNA. One day after cells were transfected, total β-hexosaminidase activity was assessed in cell culture media using th...
Data
Separation of β-hexosaminidase isoforms by anion-exchange chromatography. Samples of cerebrum were homogenized and separated by anion-exchange chromatography using a resource Q column. The first three fractions collected (column flow-through) were 1 ml each. Fractions collected during elution with a rising concentration of NaCl (100 mM–400 mM) were...
Data
Weight loss in doxycycline-inducible Sandhoff animals. (A and B) Hexb−/−HexTg and Hexb−/−SYNTg animals, respectively, put on weight steadily when fed normal lab chow (blue diamonds). When animals were fed a doxycycline laced diet from five weeks of age onward, mouse weight reached a plateau between 15 and 20 weeks of age and declined to humane endp...
Data
Production of transgenic founder mice. F2 B6CBA fertilized oocytes were microinjected with Hex or SYN constructs, outlined in red in Figure S1. Of the embryos that survived microinjection and implantation into pseudopregnant females, 10–20% of live births produced transgenic founders that had integrated the transgenic construct indicated above. Onc...
Data
Hexb−/−SYNTg mouse (−dox), one year of age. (WMV)
Data
Glycoconjugate storage in the rescued Sandhoff mouse at humane endpoint. Rescued Sandhoff mice (Hexb−/−HexTg or Hexb−/−SYNTg) in the absence of doxycycline developed residual storage of glycoconjugates, revealed with PAS staining (symbolized as red dots on the pictograms). The Hexb−/−HexTg mouse had more residual storage in the ventral forebrain (E...
Data
Hexb−/− mouse, humane endpoint. (WMV)
Data
Hexb−/−SYNTg mouse (−dox), six months of age. (WMV)
Data
Hexb−/−SYNTg mouse fed doxycycline starting at five weeks of age, viewed at humane endpoint of approximately six months of age. (WMV)
Article
Full-text available
Tay-Sachs and Sandhoff diseases are lethal inborn errors of acid β-N-acetylhexosaminidase activity, characterized by lysosomal storage of GM2 ganglioside and related glycoconjugates in the nervous system. The molecular events that lead to irreversible neuronal injury accompanied by gliosis are unknown; but gene transfer, when undertaken before neur...
Article
Full-text available
Sandhoff disease, a GM2 gangliosidosis caused by a deficiency in β-hexosaminidase, is characterized by progressive neurodegeneration. Although loss of neurons in association with lysosomal storage of glycosphingolipids occurs in patients with this disease, the molecular pathways that lead to the accompanying neurological defects are unclear. Using...
Thesis
Opiate drugs, such as codeine, morphine and heroin are powerful analgesics and drugs of abuse. The unborn child is invariably exposed to opiate drugs as a consequence of maternal use. Studies that have investigated the impact of opiate drugs demonstrated opioid system expression in proliferating regions of the developing brain, as well as on prolif...
Article
The antiproliferative effects of opiate exposure on neurogenesis in vitro have been well documented, but the effects of opiates on brain development in vivo are less well understood. We have recently shown that mu opioid receptors are expressed on radial glia of the lateral ventricle, the neuronal and glial progenitor cells of the developing cortex...
Article
Opiate drugs, such as codeine, morphine, and heroin, are powerful analgesics, but also are used as drugs of abuse because of their psychogenic properties. Many studies have shown that opiates impact on cellular proliferation in the adult and developing brain, although anatomical pathologies are lacking in in utero exposed infants and opioid knockou...
Article
Mu opioid receptor ligands such as morphine and met-enkephalin are known to modulate normal brain development by perturbing gliogenesis and inhibiting neuronal proliferation. Surprisingly, the distribution of the mu opioid receptor (MOR) in the embryonic brain, especially in proliferative regions, is poorly defined and subject to conflicting report...

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