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[초청강연] How Do Neurons Die in Neurodegenerative Diseases? : Cell Autonomous and Non-cell Autonomous Mechanisms of Neurodegeneration

2022-06-27l Hit 147

Date: 2022-06-23 11:00 ~ 13:00
Speaker: Tae-In Kam (Johns Hopkins University School of Medicine)
Professor: 생명과학부
Location: 대면 | 목암홀
How Do Neurons Die in Neurodegenerative Diseases?
: Cell Autonomous and Non-cell Autonomous Mechanisms of

Neurodegeneration
Tae-In Kam, Ph.D.

Johns Hopkins University School of Medicine

Parkinson’s disease (PD) is the second most common neurodegenerative disorder.
Intracellular protein aggregates composed primarily of α-synuclein lead to neuronal
dysfunction throughout the nervous system, ultimately accumulating in structures
designated, Lewy bodies and neurites. During the pathogenesis of PD, monomeric
α-synuclein assembles into higher ordered structures that ultimately become
pathologic and drive neuronal cell death in a cell autonomous fashion. Pathologic α-
synuclein can spread from cell to cell contributing to the progressive pathogenesis of
PD, which causes microglia- and astrocyte-mediated neuroinflammation in a non-cell
autonomous fashion. However, what drives the abnormal assembly of pathologic α-
synuclein and death in neurons as well as the neuroinflammation in non-neuronal
cells that are activated by pathologic α-synuclein are not known.
We first identified poly (ADP-ribose) (PAR) polymerase-1 (PARP-1) activation
and the generation of PAR as a key mediator of pathologic α-synuclein toxicity and
transmission in neurons. Activation of parthanatos is the primary driver of pathologic
α-synuclein neurodegeneration. Inhibition of PARP and depletion of PARP-1
substantially reduces the pathology induced by the transmission of pathologic α-
synuclein. In a feed-forward loop, PAR converted pathologic α-synuclein to a more
toxic strain and accelerated neurotoxicity both in vitro and in vivo. Consistent with the
notion that PARP-1 activation plays a role in PD pathogenesis, PAR levels were
increased in the CSF and brains of PD patients. Thus, strategies aimed at inhibiting
PARP-1 activation could hold promise as a disease modifying therapy to prevent the
loss of dopamine neurons in PD and related α-synucleinopathies. Moreover,
assessment of PAR levels in the CSF could serve as a theranostic biomarker for
disease modifying therapies in these disorders.
Growing evidence suggest that neuroinflammation is another major patho-
physiological process in PD. There is a new paradigm that activation of microglia by
classical inflammatory mediators can convert astrocytes into a neurotoxic A1
phenotype in a variety of neurological diseases. We found that α-synuclein
aggregates induce microglial activation and facilitate A1 astrocyte formation by
secreting IL-1α, TNFα and C1q, thus killing dopaminergic neurons. Moreover, we
developed a Glucagon-like peptide-1 receptor (GLP1R) agonist that protects against
the loss of dopaminergic neurons induced by α-synuclein through the direct
prevention of microglial-mediated conversion of astrocytes to an A1 neurotoxic
phenotype. In light of its favorable properties, GLP1R agonist should be evaluated in
the treatment of Parkinson’s disease and related neurologic disorders characterized
by microglial activation.