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Symposia
Molecular Mechanisms Underlying Axonal Degeneration and Synaptic Disconnection in Progressive Neurodegenerative Diseases
Chairs
Adult-onset neurodegenerative diseases include a heterogeneous group of disorders characterized by dysfunction and progressive degeneration of selected neuronal populations. Although their etiology is heterogeneous, they all share some common characteristics including a progressive development in the severity of clinical symptoms that are associated with the decline of neuronal functions. A central theme underlying these processes is selective synaptic dysfunction and subsequent neuronal disconnection, followed by a progressive dying-back pattern of axonal degeneration. Months, or even years, after the first signs of pathology, neuronal death signaling pathways are then activated leading to neuronal loss. Despite decades of intense research and a large body of cellular and molecular information, the molecular mechanisms driving those pathological features remain elusive. The goal of this symposium is to shed light on pathological mechanisms underlying progressive synaptic and axonal degeneration displayed in several adult-onset neurological disorders, including Alzheimer’s, Parkinson’s, and Tauopathies among others. Focusing on disease-specific mechanisms responsible for the initiation of neuronal dysfunction and loss, should facilitate the development of therapies aimed to preserve neuronal function and eventually to preserve the different neuronal populations affected in each disease.
Speakers
Necroaxoptosis: a degenerative mechanism involved in pathologies of the aged nervous system
Felipe Court
Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Chile
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Accumulating evidence suggest that degeneration of axons is an early event in several neurodegenerative conditions, including Alzheimer’s disease, Amyotrophic lateral sclerosis, and Parkinson’s disease. Interestingly, axonal degeneration also takes place as a consequence of healthy aging, and studies in animal models suggest that this degenerative process contributes to the loss of cognitive functions during ageing. Axonal degeneration involves destruction programs that are independent of the survival of the cell soma, and is associated to NAD+ depletion and mitochondrial dysfunction in the axonal compartment. Recently, we have demonstrated that necroptosis, a programmed cell death process, is involved in axonal degeneration after diverse stimuli as well as in models of neurodegenerative conditions, including Parkinson and Alzheimer disease. Importantly, necroptosis activation and axonal degeneration are dependent on several parameters associated to the ageing process, including a decrease in NAD+ levels in the brain, mitochondrial dysfunction and ROS production, inflammation and pathogen ligands. We propose that an age-dependent increase in the susceptibility to activation of the necroptosis machinery in neurons is associated to progressive axonal degeneration during healthy ageing, a process that can be accelerated by diverse stimuli with pathological consequences.
Molecular Mechanisms Underlying Tau Toxicity and Axonal Degeneration in Tauopathies
Nicholas Kanaan
Michigan State University
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Deposition of pathological tau is implicated in several progressive neurodegenerative disorders characterized by axonal and neuronal degeneration. Although several tau modifications are associated with sporadic disease and tau mutations cause inherited tauopathies, the molecular pathways engaged by tau to cause degeneration are still being defined. Current thinking suggests disease-related tau modifications exert toxicity by disruption of microtubules and/or enhancing aggregation. However, evidence from our group and others supports an alternative explanation. That is, tau acts to regulate signaling pathways and toxicity is due to aberrations of this function. We discovered an N-terminal motif in tau that becomes exposed in pathogenic forms of tau and causes axonal transport impairment through a protein phosphatase-1 (PP1)-dependent signaling cascade. Our hypothesis is that pathogenic tau, particularly those with abnormal conformations, cause toxicity through aberrations of a PP1-dependent mechanism. Recent work has examined the impact of pathological tau species (e.g. mutant tau and phospho-tau) on the interaction with PP1 isoforms, the activity of PP1 and axonal transport functionality in primary neurons. Our work shows that multiple forms of tau impair transport via this mechanism, by enhancing the interaction with and activity of PP1. Ongoing studies will assess whether additional pathological forms of tau affect this mechanism and other PP1-dependent neuronal processes.
Molecular mechenasim underlying synaptic disconection in Parkinson´s disease.
Gustavo Pigino
INIMEC-University of Illinois
Parkinson’s disease (PD) has been associated with a lack of communication between two neuronal populations, the substantia nigra and striatal neurons. The lack of proper communication is associated with a progressive synaptic dysfunction followed by a dying-back pattern of axonal degeneration of the substantia nigra neurons, that project and connect with striatal neurons. We propose that a vital neuronal process, required to support those affected axons known as fast axonal transport (AT) is drastically affected. Even more, we propose that this axonal transport failure triggers a progressive decrement of key biological material important for the normal synaptic and axonal functions that sustain synaptic communication and a myriad of neuronal circuitry. The identification of molecular targets that underly AT alterations promises the development of effective therapeutic strategies to treat PD, as well as other neuropathies caused by defects in axonal transport collectively termed dispheropathies. We evaluated the effect of the Parkinsonian toxin MPP+ on kinesin-1 and cytoplasmic dynein driven AT. Pharmacological and cellular biological experiments revealed increased activity of a specific axonal serine/threonine kinase activity responsible for the inhibition of the anterograde direction of AT and an increased rate of retrograde AT. In summary, alterations in bidirectional AT represent an early event in the development of PD.