Research ProgramThe purpose of our lab’s research is to develop new therapies for neurodegenerative disease. Research focuses on discovery (what is going wrong at the level of membrane?), target (how do these lipid changes affect integral membrane protein function?), diagnostics (are circulating lipids in patients biomarkers of neurodegenerative disease progression?) and therapeutics (can existing drugs and new plant-derived compounds be repurposed to treat neurodegenerative disease?).
DISCOVERY - NEUROLIPIDOMICS: MAPPING THE NEURAL LIPIDOME
RESEARCH DISCIPLINES: BIOCHEMISTRY, NEUROSCIENCE, CHEMISTRY; RESEARCH AREAS: NEURODEGENERATIVE DISEASES (ALZHEIMER'S DISEASE, PARKINSON'S DISEASE, VASCULAR DEMENTIA, CEREBROVASCULAR ACCIDENT, RARE PEDIATRIC DISEASES), CHRONOBIOLOGY, LIPIDOMICS, BIOINFORMATICS
Why are subpopulations of neurons vulnerable in Alzheimer's Disease (AD) and Parkinson's Disease (PD)? Advances in genomics have enabled researchers to identify genetic determinants of early onset disease. Direct biochemical investigations have elucidated multiple signaling pathways altered by these mutant gene products. Further combination of genomics with proteomics is allowing researchers to map global gene and protein changes associated with progressive neurodegeneration. Together, these studies have provided remarkable insight into the molecular nature of AD and PD. Despite these advances, we do not know why discrete subsets of cells are uniquely susceptible to early dysfunction nor can we protect vulnerable populations. Here, we argue that the next major advance in rational therapeutic design will come from tying a cell's metabolome into genomic and proteomic maps of disease. We argue that a "targeted systems approach" will provide a new understanding into the metabolic regulatory mechanisms that determine why groups of cells become transiently susceptible and finally succumb to genetic and environmental determinants of AD and PD. Such insight will provide new therapeutic avenues designed to protect vulnerable neuronal populations in the face of ongoing insult.
Why lipids? Lipids are the building blocks of biological membranes and make up half the wet weight of brain tissue. They modulate membrane trafficking. They transduce intracellular signalling pathways. While commonly studied in families (e.g., diacylglycerols, glycerophospholipids, cholesterols), individual isoforms display unique properties that differentially regulate cellular responses to external and internal stimuli. Certainly, AD and PD are, in large part, mediated by changes in lipid metabolism with disruptions in glycerophospholipid, cholesterol, arachidonic acid, and phosphatidylinositol-4,5-bisphosphate metabolism associated with accelerated cognitive decline. Mechanistic insight, however, has been complicated by the considerable technical challenges associated with distinguishing pathogenic from non-pathogenic lipid species within samples containing several thousand isoforms.
The field of lipidomics seeks to address this issue. Lipidomics defines "the large-scale analysis of lipid profiles in cells and tissues". Neurolipidomics focuses on cellular, regional, and systemic lipid homeostasis in the central nervous system encompassing not only the identification and measurement of individual lipid isoforms but also the mRNA and protein expression profiles of metabolic enzymes and transporters and the protein targets that affect downstream signalling in neurons and glia. Further, a lipidomic analysis also includes an unbiased assessment of lipid function ranging from the physicochemical basis of lipid behaviour to lipid-protein and lipid-lipid interactions, and impact of dynamic lipid metabolism on cellular response to intrinsic and extrinsic stimuli.
TARGET - INTEGRAL MEMBRANE PROTEIN FUNCTION: DIRECTING NEURAL STEM CELL FATE AND TARGETING LIPID SIGNALLING PATHWAYS
RESEARCH DISCIPLINES: BIOCHEMISTRY, NEUROSCIENCE, PHARMACOLOGY, CELL BIOLOGY, MOLECULAR BIOLOGY; RESEARCH AREAS: NEURODEGENERATIVE DISEASES (ALZHEIMER'S DISEASE, PARKINSON'S DISEASE, EPILEPSY), ADULT NEURAL STEM CELLS, PLASTICITY AND NEUROREGENERATION, HORMONAL REGULATION, LIPIDOMICS, SUPER-RESOLUTION MICROSCOPY
Neuroregeneration: Clinical trials hint at the potential of stem cell replacement strategies as stroke therapy yet longitudinal studies are conspicuous in their absence. Experimental evidence warns that activation of resident neural stem and progenitor cells (NPCs) in injured tissue can result in the integration of inappropriate cell types into damaged circuits causing further neurological complications. Attention must also be paid to the possibility that tumour stem cells can arise from the transformation of NPC populations in diseased tissue. Clearly, validation of cell replacement strategies will depend upon a comprehensive understanding of how appropriate cell lineages are effectively generated in injured brain.
Neurodegeneration: Two central pathologies define Alzheimer's Disease (AD): (1) intraneuronal accumulation of neurofibrillary tangles composed of hyperphosphorylated tau and (2) aberrant processing of the amyloid precursor protein (APP) to toxic amyloid beta (Abeta fragments. The most damaging is Abeta42. Accumulation is gradual with assembly of soluble Abeta oligomers impairing synaptic function and signalling synaptic loss The 'amyloid hypothesis' defines these events as the root cause of AD. Yet, despite strong proofs that Abeta and tau aggregations are driving pathologies, converging evidence suggests that they likely represent only two of multiple determinants necessary for AD memory impairment. This refinement is based on evidence that Abeta42 accumulation (at AD load levels) can be found in cognitively 'normal' elderly as well as humanized mouse models of Abeta42/tau accumulation with little manifestation of memory deficits. These observations have prompted a 're-imagining' of the amyloid hypothesis (Karl Herrup). Here, the amyloid deposition cycle, aggravated by chronic neuroinflammation, triggers a critical 'change in state'. This 'change of state' is envisioned as a convergence of metabolic disruptions that result in "a new 'normal' biology primed towards neurodegeneration and dementia". Targeting these metabolic determinants represents a novel, potentially transformative, approach to prevent AD conversion.
DIAGNOSTICS - LIPID STATE, RATE, TRAIT AND FATE BIOMARKERS FOR NEURODEGENERATIVE DISEASE
RESEARCH DISCIPLINES: BIOCHEMISTRY, NEUROSCIENCE, CHEMISTRY; RESEARCH AREAS: NEURODEGENERATIVE DISEASES (ALZHEIMER'S DISEASE, PARKINSON'S DISEASE), GENETICS OF NEUROLOGICAL AND PSYCHIATRIC DISEASES, LIPIDOMICS, BIOSTATISTICS
There are no disease mechanism(s)-associated laboratory-based biomarkers in clinical use for Dementia with Lewy Bodies (DLB), Parkinson's Disease with Dementia (PDD), or Parkinson's Disease (PD). This void is detrimental to the diagnosis of our patients and their proper stratification in clinical trials. It also precludes the development of cause-directed treatment. 'State, rate, fate, and trait' biomarkers are urgently needed to improve early diagnosis (state), track disease progression (rate), predict critical endpoints (fate), and identify risk in pre-symptomatic persons (trait).
Heterozygous mutations in GBA1, the gene encoding the enzyme beta-glucocerebrosidase (GCase), increase risk of cognitive impairment in alpha-synucleinopathies but not AD. GCase hydrolyzes glycosylceramide to glucose, ceramide, and sphingosine. Converging evidence implicates aberrant sphingolipid metabolism in both cognitive phenoconversion and disease progression. Thus, our goal is to identify and validate blood- and/or cerebrospinal fluid-based sphingolipid 'state, rate, fate' biomarkers for DLB, PDD, and PD. We apply an interdisciplinary approach capitalizing on our teams' (a) expertise in translational lipidomics, (b) unprecedented access to PD, PDD, Alzheimer's Disease (AD), DLB, DLB+AD, PD+AD patient (and age-matched control) cohorts, (c) ongoing lipidomic and alpha-synuclein assessment of post-mortem brain tissue, and (d) development of the first bi-genic mouse model of PD/DLB to compare circulating and central lipid profiles as validate critical indicators of neurodegenerative disease."
THERAPEUTICS - REPURPOSING TRADITIONAL AND NON-TRADITIONAL MEDICINES TO PROVIDE ADJUVANT TREATMENTS FOR NEURODEGENERATIVE DISEASE
RESEARCH DISCIPLINES: BIOCHEMISTRY, NEUROSCIENCE, MEDICINAL CHEMISTRY, PEDIATRICS, PHARMACOLOGY, CELL BIOLOGY, DIETETICS AND NUTRITION, MOLECULAR BIOLOGY; RESEARCH AREAS: NEURODEGENERATIVE DISEASES (ALZHEIMER'S DISEASE, PARKINSON'S DISEASE, EPILEPSY), GENETICS OF NEUROLOGICAL AND PSYCHIATRIC DISEASES, BRAIN METABOLISM, ADULT NEURAL STEM CELLS, PLASTICITY AND NEUROREGENERATION, DIABETES, LIPIDOMICS
Our ultimate goal is to bring our discovery, target, and diagnostic research programs to clinic. Thus, a subset of NRL team members focus on identifying clinically approved drugs and medicines used by traditional healers that modify lipid and target molecule signalling and repurposing these compounds to potentially treat neurodegenerative diseases. Using patient fibroblasts, human neurons derived from induced pluripotent stem cells reprogrammed from patients as well as genetically matched familial controls, transgenic mouse models of human disease, and patient-specific mouse models of rare pediatric neurodegenerative diseases, we seek to (i) identify compounds that normalize levels of critical lipid indicators and/or modulate their signalling pathways and (ii) establish whether these compounds (a) reduce neuro- and gliotoxicity, (b) direct neural stem cell fate to facilitate regeneration, and/or (c) compensate for aberrant lipid metabolism to reduce the rate of phenoconversion (onset of cognitive decline) in vitro and in vivo. In the process, we develop and validate new preclinical animal models of neurodegenerative disease.