Transcript Auto-fluorescent aggregates can be found in CHMP2B Intron5 mice

Presenter: Paul Chang (張保盛)
20160428
Dementia’s Statistics
http://www.prb.org/Publications/Articles/2012/global-dementia.aspx
Outline
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What is Frontotemporal Dementia?
Background of this article
What makes this article so special?
Discussion and Summary
Q&A
Different aspects of dementia
http://medschool.ucsf.edu/features/examining-link-between-early-stage-dementia-and-criminal-behavior
What is Frontotemporal Dementia
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Neuronal loss in frontal and temporal lobe
Genetic inheritance
Mostly diagnosed in young age
Emotional disability
Speech and language disorder
https://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=167
Background of this article
• FTP is frequently caused by genetic mutations in:
MAPT, GRN and C9orf72
• Some rare mutations are involved such as:
VCP, TDP-43, FUS and CHMP2B
http://www.nutraingredients-usa.com/Research/Omega-3-may-reduce-the-risk-of-neurodegenerative-diseases
Background of this article
• Charged Multi-vesicular Body Protein 2B (CHMP2B) is a
subunit of the Endosomal Sorting Complex Required for
Transport Ⅲ (ESCRT-Ⅲ)
http://jcb.rupress.org/content/185/2/185/F1.expansion.html
Background of this article
• Mutant CHMP2BIntron5 has been shown to affect the
maturation of both endosomes and auto-phagosomes
Endo-lysosomal System
http://www.nature.com/nrn/journal/v6/n9/box/nrn1725_BX1.html
Background of this article
• Mice with mutant CHMP2BIntron5 show progressive gliosis
and p62 inclusion pathology, as well as in human beings
http://archives.biotecnika.org/content/january-2013/shifting-balance-between-good-fat-and-bad-fat-p62-protein
http://ntp.niehs.nih.gov/nnl/special_senses/eye/onglios/index.htm
What makes this article so special?
FTD patient
CHMP2B Mutation
Caused by CHMP2B
Mutation
Caused by normal aging
What makes this article so special?
In patient’s frontal cortex
Result 1
Auto-fluorescent aggregates can be found in
CHMP2BIntron5 mice
Result 1: Auto-fluorescent aggregates can be
found in CHMP2BIntron5 mice
In thalamus
Result 1: Auto-fluorescent aggregates can be
found in CHMP2BIntron5 mice
In cortex
Result 2
Auto-fluorescent aggregates are distinct from
p62 inclusions in CHMP2BIntron5 mice
Result 2: Auto-fluorescent aggregates are distinct
from p62 inclusions in CHMP2BIntron5 mice
In thalamus
Result 2: Auto-fluorescent aggregates are distinct
from p62 inclusions in CHMP2BIntron5 mice
Low Pearsons correlation co-efficient means that p62
inclusions and auto-fluorescent aggregates are less co-localized
with each other
Result 3
CHMP2BIntron5 auto-fluorescent aggregates occur
in neurons and microglia
Result 3: CHMP2BIntron5 auto-fluorescent
aggregates occur in neurons and microglia
In thalamus
However, p62 inclusions exist mostly in
oligodendrocytic processes (stained by CA ll)
In contrast to auto-fluorescent aggregates, p62 inclusions predominantly occur in
the hippocampus rather than the frontal cortex in FTD patient’s brain.
Result 4
CHMP2BIntron5 neuronal aggregates associated
with the endo-lysosomal system
Result 4: CHMP2BIntron5 neuronal aggregates
associated with the endo-lysosomal system
Multi-vesicular body
Lamellar membrane whorls
Result 4: CHMP2BIntron5 neuronal aggregates
associated with the endo-lysosomal system
Result 4: CHMP2BIntron5 neuronal aggregates impair
the endo-lysosomal system
Discussion
• The excitation/emission spectra of auto-fluorescent
aggregates should be well-defined
• The role of p62 inclusions compared with the autofluorescent aggregates
• Is lipofuscin a precursor of the auto-fluorescent
aggregate?
Summary
• Auto-fluorescent aggregates can be found in the thalamus
and cortex of CHMP2BIntron5 mice
• The existing pattern of auto-fluorescent aggregates is
distinct from p62 inclusions in CHMP2BIntron5 mice
• The neuronal aggregates of CHMP2BIntron5 mutant are
associated with the endo-lysosomal system
Auto-fluorescent Protein
• The natural emission of light by biological structures but
not originating from the artificially added fluorescent
markers
• Spectral Imaging with Subsequent Linear Unmixing
technique is used to distinguish the signals between the
auto-fluorescence and the artificially labelled secondary
antibody.
https://en.wikipedia.org/wiki/Autofluorescence