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Principal Investigator: Christopher D Deppmann
Organization: UNIVERSITY OF VIRGINIA
Fiscal Year: 2024
Award: $450,552
Funding agency: National Institute of Neurological Disorders and Stroke
Summary:
Axon degeneration occurs during development of the nervous system as well as neuropathologies including
Alzheimer's, Luo Gehrig's, and Huntington's disease as well as stroke, and spinal cord injury. A common but
poorly defined feature of all forms of neural degeneration is the emergence of swellings or spheroids that appear
prior to irreversible breakdown of the axon. These degenerative spheroids were first observed in the early 1900's
by Cajal but their function has gone undescribed until our recent work. We found that in both developmental and
pathological contexts, diverse degenerative triggers converge on spheroid formation. In both contexts, spheroids
grow to the point of rupture and their contents hasten irreversible axon breakdown in an autocrine and paracrine
manner. This suggests that spheroids are not merely a morphological hallmark of degenerating axons but also
perform a critical function that may be universal to all forms of axon degeneration. We also suggest that spheroid
formation and rupture demarcates the transition from latent to catastrophic phases of axon degeneration. In Aim
1, we characterize the properties of spheroid formation (e.g. growth, movement, fusion, and rupture) as well as
the signaling pathways that control spheroid formation. In Aim2, we examine the pathways downstream of
spheroid rupture in regulating catastrophic axon degeneration. Finally, in Aim3, we determine whether mouse
lines with impaired Wallerian degeneration but intact (DR6-/- and Sarm1-/-) or deficient (Wlds) spheroid formation
influences recruitment of macrophages and regenerative capacity. Understanding how spheroids are formed
and how their contents induce catastrophic axon breakdown represents an important avenue toward developing
therapeutics for nervous system degeneration. Our expertise in mouse genetics, developmental neuroscience,
cytokine signaling, and biochemical analysis places us in a unique position to delineate mechanisms that have
eluded the field for decades.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><AD dementia><Acute><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Amyotrophic Lateral Sclerosis><Amyotrophic Lateral Sclerosis Motor Neuron Disease><Apoplexy><Assay><Autocrine Systems><Axon><Bioassay><Biochemical><Biogenesis><Biological Assay><Brain Trauma><Brain Vascular Accident><C-jun Amino-Terminal Kinase><C-jun Kinase-1><C-jun N-Terminal Kinase 1><Ca2+-Activated Protease><Cachectin Receptors><Calcium><Calcium-Activated Neutral Protease><Calcium-Activated Neutral Proteinase><Calcium-Activated Protease><Calcium-Dependent Neutral Protease><Calcium-Dependent Neutral Proteinase><Calpain><Caspase><Caspase Gene><Catabolism><Cell Communication and Signaling><Cell Signaling><Cell-Death Protease><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cessation of life><Chronic><Co-culture><Cocultivation><Coculture><Coculture Techniques><Cues><Cysteine Endopeptidases><Cysteine Protease><Cysteine Proteinases><Cytokine Signal Transduction><Cytokine Signaling><Death><Degenerative Neurologic Disorders><Desminase><Development><Dihydronicotinamide Adenine Dinucleotide><Diphosphopyridine Nucleotide><Disparate><Eating><Event><Family member><Food Intake><Gehrig's Disease><Generalized Growth><Growth><Huntington Chorea><Huntington Disease><Huntington's><Huntington's Disease><Huntingtons Disease><ICE-like protease><Impairment><Infiltration><Injury><Intracellular Communication and Signaling><JN Kinase><JNK><JNK Mitogen-Activated Protein Kinases><JNK1><JNK1 Kinase><JNK1 protein><JNK1A2><JNK21B1/2><Kinetics><Lou Gehrig Disease><MAP Kinase 8><MAP Kinase 8 Gene><MAPK8><MAPK8 Mitogen-Activated Protein Kinase><MAPK8 gene><Macropain><Macrophage><Macroxyproteinase><Mice><Mice Mammals><Microfluidic Device><Microfluidic Lab-On-A-Chip><Microfluidic Microchips><Microfluidics><Mitogen-Activated Protein Kinase 8><Modeling><Molecular><Morphology><Movement><Multicatalytic Proteinase><Murine><Mus><Mutant Strains Mice><Mφ><Nadide><Natural regeneration><Nerve Cells><Nerve Crush><Nerve Degeneration><Nerve Unit><Nervous System><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Body System><Neurologic Degenerative Conditions><Neurologic Organ System><Neuron Degeneration><Neurons><Neurosciences><Nicotinamide adenine dinucleotide><Nicotinamide-Adenine Dinucleotide><Origin of Life><PRKM8><Papain-Like Cysteine Protease><Paralysis Agitans><Parkinson><Parkinson Disease><Pathologic><Pathway interactions><Phagocytes><Phagocytic Cell><Phase><Phenotype><Phosphatidylserines><Position><Positioning Attribute><Primary Parkinsonism><Primary Senile Degenerative Dementia><Property><Prosome><Proteasome><Proteasome Endopeptidase Complex><Proteosome><Receptor Protein><Regeneration><Regenerative capacity><Regulation><Role><Rupture><SAP Kinase-1><SAPK/JNK><SAPK1 Mitogen-Activated Protein Kinase><SAPK1/JNK><Serine Phosphoglycerides><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Spinal Cord Trauma><Spinal Trauma><Spinal cord injured><Spinal cord injury><Stress-Activated Protein Kinase JNK1><Stress-Activated Protein Kinase gamma><Stroke><Structure><Swelling><TNF Receptor Family Protein><TNF Receptor Superfamily><TNF Receptors><TNFR><Techniques><Therapeutic><Therapeutic Intervention><Tissue Growth><Translations><Traumatic Brain Injury><Traumatic Myelopathy><Tumor Necrosis Factor Receptor><Tumor Necrosis Factor Receptor Family><Tumor Necrosis Factor Receptor Superfamily><Wallerian Degeneration><Wild Type Mouse><Withdrawal><Work><amebocyte><autocrine><axon regeneration><axonal degeneration><axonal regeneration><biological signal transduction><body movement><brain attack><c-jun N-Terminal Kinase><cerebral vascular accident><cerebrovascular accident><cystein protease><cystein proteinase><cysteine endopeptidase><degenerative axon><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><deprivation><developmental><experiment><experimental research><experimental study><experiments><gain of function><in vivo><in vivo regeneration><inhibitor><injured><injuries><injury response><intervention therapy><jun-NH2-Terminal Kinase><loss of function><microfluidic chip><mouse genetics><mouse mutant><multicatalytic endopeptidase complex><mutant><nerve cell death><nerve cell loss><nerve injury><nervous system development><neural degeneration><neural injury><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neurological pathology><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal degeneration><neuronal loss><neuropathologic><neuropathological><neuropathology><novel><ontogeny><paracrine><pathway><pharmacologic><preservation><prevent><preventing><primary degenerative dementia><programs><receptor><recruit><regenerate><regeneration ability><regeneration capacity><response><response to injury><rho><sciatic nerve><secondary degeneration><senile dementia of the Alzheimer type><social role><spheroids><stress-activated protein kinase 1><stroked><strokes><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><translation><traumatic brain damage><wasting><wildtype mouse><µfluidic>