Download Molecular Mechanisms of Neurodegeneration Course Directors: Einar M. Sigurdsson, Ph.D. Jorge Ghiso, Ph.D.

Molecular Mechanisms of Neurodegeneration
Course Directors:
Einar M. Sigurdsson, Ph.D.
Jorge Ghiso, Ph.D.
Course Description:
This elective course for graduate students focuses on molecular and cellular mechanisms of
neurodegeneration. Various topics will be covered as outlined below. For the Spring 2015
semester, these include, genetics, endoplasmic reticulum stress, endosomal dysfunction,
parenchymal and vascular amyloid as well as cerebrovascular dysfunction, axonal degeneration,
mitochondria and oxidative stress, viral infections, neuromuscular synapses, microglia and
therapeutic approaches. It is anticipated that these topics may change from year to year based on
advances in the field and availability of experts. The objective is to provide students who are
interested in neurodegeneration with a foundation relevant to their dissertation project, and that
these lectures and journal clubs may introduce them to novel concepts, hypotheses and
controversies that may have implications for their own research.
Endoplasmic Reticulum Stress and Neurodegeneration
Don Ryoo, Ph.D.
Endoplasmic reticulum (ER) is a subcellular organelle where most membrane and secretory
proteins are synthesized and undergo protein folding. Interestingly, there are many conditions
that impair the folding properties of proteins in this organelle that underlie neurodegenerative
diseases. In this lecture, I plan to cover our current understandings of the molecular events that
link stress in the ER to neurodegeneration. First, I plan to cover the well-established signaling
responses to excessive ER stress. Certain branches of such "Unfolded Protein Response" have
been implicated in actively inducing cell death, and therefore, underlie neurodegeneration.
Second, I plan to review an alternative view that implicates Ca2+ in mediated signaling. ER is in
fact a major storage organelle for Ca2+, and according to this view, excessive stress in this
organelle would lead to leakage of Ca2+ that triggers death signaling. Certain studies further
indicate that the downstream signaling actively promotes neuronal necrosis through a poorly
understood mechanism.
Microglia Function in Synaptic Plasticity and Pathology.
Wenbiao Gan, Ph.D.
Microglia are the brain’s tissue macrophages and the primary immune effectors within the CNS.
They are highly dynamic, responsible for normal tissue maintenance and respond rapidly to
perturbations within the brain. In pathologic conditions, activated microglia undergo
morphological changes and produce cytokines and chemokines that affect surrounding cells.
In the lecture, I will introduce where microglia come from and how they might be involved in
synapse development, plasticity and pathology.
Mechanisms of HIV-Induced Cognitive Decline and Depression
Edward Ziff, Ph.D.
The Human Immunodeficiency Virus (HIV), consisting of RNA and protein, can enter the body,
infect cells of the immune system, replicate and destroy immune defenses. Highly Active
Antiretroviral Therapy (HAART) has greatly prolonged the lives of AIDS patients. As AIDS
patients live longer, the virus can infect the central nervous system and cause severe neurological
problems. The neurological problems include cognitive decline and depression. HIV/AIDS
infection of the nervous system presents new challenges for following the progress of the disease
and for treatment. The lecture will consider the mechanisms of HIV-induced cognitive decline
and depression including the excitotoxic properties of the viral gp120 and Tat proteins and the
role of inflammatory cytokines in HIV depression.
Contribution of Endosomal Dysfunction to Neurodegenerative Disorders
Paul Mathews, Ph.D.
The neuronal endosomal system is a point of vulnerability in numerous neurodegenerative
disorders, ranging from Alzheimer’s disease (AD) and Down syndrome to amyotrophic lateral
sclerosis (ALS), CHMP2B-frontotemporal dementia and Niemann Pick type C disease. The
endocytic pathway sequesters material from the extracellular space and plasma membrane for
processing within endocytic vesicle and can target materials for degradation in lysosomes or cellto-cell transport via exosomes. Endocytosis plays a central role in modulating the plasma
membrane availability of receptors and transporters, the uptake, processing and generation of
substrates for energy and biosynthetic processes, as well as eliminating damaged, potentially
toxic materials through the lysosome. The causes of neurodegenerative endosomal system
disruption can be multifactorial, arising in some cases through genetic mutations, and potentially
further driven by environmental factors such as lipid/cholesterol load. Indeed, changes in
membrane cholesterol and lipids are associated with defects in endosomal function in multiple
neurodegenerative diseases, including Niemann-pick disease, AD, Huntington’s disease, and
Parkinson’s disease. Finally, the endocytic system may serve a key role in the propagation of
pathology from one cell to another, both through the uptake of pathogenic proteins into healthy
cells as well as the secretion of pathologenic molecules from a compromised cell.
The Cerebrovascular System and Neurodegeneration
Jorge Ghiso, Ph.D.
The CNS possesses a highly specialized vasculature that provides sensitive neurons with a
controlled environment free of toxic metabolites and pathogens. This protection is achieved by
the blood-brain barrier –a highly selective permeability barrier that separates the circulating
blood from the brain extracellular fluid– formed by capillary endothelial cells displaying
specialized tight junctions and exhibiting extremely low rates of trans-cellular vesicular
transport. The specific function of the barrier is regulated by a cross-talk between neural and
vascular cells, constituting the so-called neurovascular unit. Breakdown of the blood-brain
barrier is associated with the initiation and perpetuation of various neurological disorders. This
session will cover the molecules and mechanisms responsible for blood-brain barrier
homeostasis and how perturbations in their function are involved in the process of
neurodegeneration.
Mitochondrial dysfunction and Oxidative Stress in Neurodegeneration
Giovanni Manfredi, M.D., Ph.D.
A growing body of evidence suggests that mitochondrial dysfunction plays a role in the
pathogenesis of various neurodegenerative disorders. The lecture will provide insights into the
mechanisms regulating energy metabolism, impairment of the respiratory chain, and reduction
in ATP synthesis. The role of point mutations and rearrangements in mitochondrial DNA for
the pathogenesis of a heterogeneous group of sporadic, mendelian, or maternally-inherited
mitochondrial disorders will be discussed. The use of cybrid cells to study complex aspects of
mitochondrial biology in health and disease will be highlighted
Congenital and Autoimmune Myasthenia: Dysfunction & Disassembly of Neuromuscular
Synapses
Steven Burden, Ph.D.
This session will cover the molecules and mechanisms that are responsible for forming and
maintaining neuromuscular synapses and how perturbations in their function, caused by
mutations or autoantibodies, causes defects in the synaptic transmission and neuromuscular
disease.
Dysregulated Translational Control in Neurodegenerative Disease
Eric Klann, Ph.D.
A requirement for de novo protein synthesis is one of the hallmarks of long-lasting synaptic
plasticity and long-term memory. Numerous studies, including several from our laboratory, have
identified signaling cascades that couple cell surface receptors to the translation regulatory
machinery during the formation of long-lasting synaptic plasticity and the consolidation of longterm memory. Notably, alterations in markers of translational control have been observed in
postmortem brains in humans with neurodegenerative diseases, as well as in mouse models of
these diseases. I will discuss studies mechanisms of translational control in the normal brain and
how these mechanisms are dysregulated in mouse models of neurodegenerative diseases,
including Alzheimer's disease.
Genetics of Neurodegenerative Diseases
Naoko Tanese, Ph.D.
The lecture will cover etiologies of hereditary neurodegenerative diseases such as repeat
expansion diseases including Huntington disease, fragile X mental retardation syndrome,
myotonic dystrophy, and various forms of ataxias. Recent studies suggest RNA-related
mechanisms may contribute to disease pathogenesis. Abnormalities in RNA processing can
result in production of toxic RNA species and mutations in RNA binding proteins can alter RNA
metabolism. Disease mechanisms involving RNA may be a common theme among many
neurodegenerative disorders.
Brain Parenchymal Amyloids
Einar M. Sigurdsson, Ph.D.
The lecture will cover the cellular and molecular mechanisms of parenchymal aggregation and
associated toxicity of various protein and peptides with a particular focus on the amyloid-β
peptide and the tau protein. Current therapeutic and diagnostic approaches will be discussed as
well.
Pharmaceutical Approaches to Neurodegeneration
Moses Chao, Ph.D.
In the last two decades, the genes responsible for familial Alzheimer’s disease, Parkinson’s
disease, Huntington’s disease, motor neuron disease and other neurodegenerative disorders
have been identified. However, the key pathological events and rational targets for therapeutic
intervention are elusive. Also, many large pharmaceutical companies have abandoned
neuroscience drug discovery. Increasing evidence indicates that the mechanisms underlying
neurodegeneration may be shared among different disorders. This lecture will address previous
pharmaceutical attempts and new emerging areas in neurodegenerative disease research that
reveal novel mechanisms and approaches for therapeutic intervention.
Axonal Degeneration
James Salzer, M.D, Ph.D.
Degeneration of axons is a key contributor to the morbidity of a wide array of neurological
disorders that includes injury, neurodegeneration, and demyelinating disorders. We will review
recent studies into the mechanisms of axonal degeneration and clearance that are emerging from
tissue culture studies of Wallerian degeneration and genetic screens in model organisms. We
will also discuss the neuroprotective role of glia. Finally, recent studies that suggest axonal
injury reprograms the neuronal soma and distal glia for axonal regeneration will be described.
Technical lectures
Computational approaches for predicting/designing protein and peptidomimetic structures
Richard Bonneau, Ph.D.
Novel proteomic approaches with applications to the field of neuroscience.
Thomas Neubert, Ph.D.
Bioinformatics in the "Omics" era.
David Fenyo, Ph.D.
Suggested schedule:
Ninety minutes twice per week, lecture and journal club on a related topic.
Grade:
Class participation (30%), miniature NIH format grant proposal (40%), journal club presentation
(30%).
Molecular Mechanisms of Neuordegeneration 2015
Wednesday, January 21 Smilow 601A 10:00-11:30am
Friday, January 23
MSB 588
11:00am-12:30pm
Wednesday, January 28 Smilow 601A 10:00-11:30am
Friday, January 30
MSB 588
10:00-11:30am
Wednesday, February 4 Smilow 601A 10:00-11:30am
Friday, February 6
MSB 588
10:00-11:30am
Wednesday, February 11 Smilow 601A 10:00-11:30am
Friday, February, 13
MSB 588
10:00-11:30am
Wednesday, February 18 Smilow 601A 10:00-11:30am
Friday, February 20
MSB 588
10:00-11:30am
Wednesday, February 25 Smilow 601A 10:00-11:30am
Friday, February 27
MSB 588
11:00am-12:30pm
Wednesday, March 4
Smilow 601A 10:00-11:30am
Friday, March 6
MSB 588
10:00-11:30am
Wedensday, March 11
Smilow 601A 10:00-11:30am
Friday, March 13
MSB 588
10:00-11:30am
Wednesday, March 18
Smilow 601A 10:00-11:30am
Friday, March 20
MSB 588
10:00-11:30am
Wednesday, March 25
Smilow 601A 10:00-11:30am
Friday, March 27
MSB 588
11:00am-12:30pm
Wednesday, April 1
Smilow 601A 10:00-11:30am
MSB 588
10:00-11:30am
Friday, April 3
Smilow 601A 10:00-11:30am
Wednesday, April 8
MSB 588
10:00-11:30am
Friday, April 10
Smilow 601A 10:00-11:30am
Wednesday, April 15
MSB 588
10:00-11:30am
Friday, April 17
Smilow 601A 10:00-11:30am
Wednesday, April 22
MSB 588
11:00am-12:30pm
Friday, April 24
Smilow 601A 10:00-11:30am
Wednesday, April 29
MSB 588
10:00-11:30am
Friday, May 1 W
Lecture Title
Endoplasmic Reticulum Stress and Neurodegeneration
Microglia function in synaptic plasticity and pathology
Mechanisms of HIV-induced congitive decline and depression
Grant writing
Technical lecture
Technical lecture
Technical lecture
Contribution of endosomal dysfunction to neurodegenerative
disorders
The cerebrovascular system and neurodegeneration
Mitochondria and oxidative stress in neurodegeneration
Congenital and autoimmune Myasthenia:
Dysfunction & disassembly of neuromuscular synapses
Dysregulated translational control in neurodegenerative disease
Genetics of neurodegenerative diseases
Brain parenchymal amyloids
Neuroscience retreat - No class
Neuroscience retreat - No class
Pharmaceutical approaches to neurodegeneration
Axonal degeneration
Lecturer
Hyung Don Ryoo
Hyung Don Ryoo
Wen-biao Gan
Wen-biao Gan
Ed Ziff
Ed Ziff
Jorge Ghiso and Einar Sigurdsson
Richard Bonneau
Thomas Neubert
David Fenyo
Paul Mathews
Paul Mathews
Jorge Ghiso
Jorge Ghiso
Giovanni Manfredi
Giovanni Manfredi
Steve Burden
Steve Burden
Eric Klann
Eric Klann
Naoko Tanese
Naoko Tanese
Einar Sigurdsson
Einar Sigurdsson
Moses Chao
Moses Chao
Jim Salzer
Jim Salzer