Studies On The Role Of Mitochondrial Dysfunction In Amyloid- β Mediated Neurodegeneration
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
Studies On The Role Of Mitochondrial Dysfunction
In Amyloid- β Mediated Neurodegeneration
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| Creator |
DAS, HRISHITA
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| Subject |
Cell Biology & Physiology
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| Description |
Alzheimer’s disease (AD) is one of the major causes of dementia worldwide. AD is
characterized clinically by progressive cognitive decline, and pathologically by the presence of
extracellular senile plaques composed primarily of amyloid-β peptide (Aβ) and intracellular
neurofibrillary tangles made up mainly of hyper phosphorylated tau.AD is a progressive disease
and may takes more than twenty years to develop prominent clinical symptoms such as memory
loss. It is important to unfold early molecular mechanisms that contribute to development of the
disease.Aberrant accumulation of amyloid-β (Aβ) in brain is the major trigger for pathogenesis
in AD. It is hence essential to understand how Aβ attains such toxic levels in the brain
parenchyma. Aging is one of the major risk factors of AD. DNA damage plays an important role
both in aging and AD. We studied the effect of both toxic and sub lethal dose of DNA damage
on neurons. Treating differentiated SH-SY5Y cells with a toxic dose of Camptothecin(CPT)
induced ROS, mitochondrial dysfunction and apoptosis. Increased expression of BID which is a
BH3-only pro-apoptotic protein was observed under similar treatment. Down regulation of BID
provided transient protection from toxic dose of CPT in neurons.
Next we shifted our focus to study the stress response in neuron induced by sub lethal dose of
DNA damaging agent CPT and Doxorubicin (Dox) without inducing cell death.We detected that
a very subtle and tolerable amount of DNA damage, related to aging, increased intraneuronal
Aβ1-42 production both in cultured neuron and in the cortex of rodent brain.Strikingly, we also
observed elevated levels of mitochondrial fusion and of its major driver protein, MFN2.
Hyperfusion of mitochondria may be seen as an adaptive stress response resulting from the
induction of ER stress since we detected upregulated phosphorylation of both PERK, an
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important arm of unfolded protein response and an ER-stress marker, and its substrate eukaryotic
initiation factor 2 α (eIF2α), together constituting a signaling responsible for protective
mitochondrial remodeling. This adaptive remodeling of mitochondria resulted in an increase in
mitochondrial oxygen consumption rate and ATP production. At later time points this elongated
structure of mitochondria shifts towards fission. Mitochondrial fission is observed in AD brain
but the phenomenon that is leading to this shift is not well studied in the disease model. Reports
suggest that eIF2α phosphorylation can increase BACE1 activity, the rate limiting enzyme in Aβ
production. In our model, we show that inhibiting PERK, decreased Aβ1-42 level while direct
BACE1 inhibition, reduced the mitochondrial fusion.Moreover, we found increased MFN2
expression in younger 5xFAD transgenic mice when Aβ plaques and neurodegeneration were
absent. Down regulation of MFN2 decreased CPT induced increase in Aβ1-42in neuron. Thus, this
study indicates that mild DNA damage leads to increased Aβ1-42 production via ER stress and
may also direct mitochondrial elongation as an initial adaptive/protective response. We propose
that age-related subtle genomic DNA damage may trigger enhanced intraneuronal Aβ1-
42 production in an apparently healthy neuron way before the appearance of clinical symptoms in
AD.
Mitochondrial genome can bear signatures for AD. Mutation in mitochondrial genome can
compromise its function and also can be considered as biomarker for early diagnosis of the
disease. In the next part of our work we have analysed point mutations in mtDNA from AD
patient’s whole blood. We identified SNPs which are common and unique to all the samples. The
nature and distribution of mutations were also studied. To our surprise the mutations were not
due to oxidation, but it was due to replication error. The SNPs were dispersed in coding region
not in D loop of mtDNA. Defective replication of mtDNA could be a result of ineffective
replication carried by POLG. Further work in this direction will help to understand the reason of
developing these mutations in AD patients’ whole blood.
Altogether this work explores an unconventional role of mitochondria in AD. The connection of
mitochondria in subtle DNA damage associated stress response and increase in Aβ1-42 production
in neuronsis a novel finding and may lead to better understanding of the pathogenesis of AD.
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| Date |
2021
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| Type |
Thesis
NonPeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2835/1/Thesis_for_Evaluation_Hrishita_Das.pdf
DAS, HRISHITA (2021) Studies On The Role Of Mitochondrial Dysfunction In Amyloid- β Mediated Neurodegeneration. PhD thesis, UNIVERSITY OF CALCUTTA. |
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| Relation |
http://www.eprints.iicb.res.in/2835/
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