Role Of Pro-Apoptotic Proteins In Autophagy In Neurodegenerative Diseases
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
Role Of Pro-Apoptotic Proteins In Autophagy
In Neurodegenerative Diseases
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| Creator |
Saha, Akash
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| Subject |
Cell Biology & Physiology
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| Description |
Alzheimer’s disease (AD) is the most common forms of dementia affecting the elderly
people worldwide. It is a progressive, multifaceted and degenerative disease which leads
to loss of synapse and eventually neuron death in the associated regions of the brain like
the cerebral cortex, hippocampus and amygdala. Accumulation of oligomeric amyloid
beta (Aβ) leading to deposition of senile plaques, which in turn may trigger the
hyperphosphorylation of tau leading to neurofibrillary tangles, is supposed to be the
main pathological hallmark of the disease. However, with recent developments it is
reported that there is an overall dysfunction of the homeostasis in the brain milieu
including loss of vasculature, aberrant microglial and astrocytes functioning, referred to as
the cellular phase of AD. The two major death paradigms among the many that are
reported to cause neuronal death in AD are apoptosis and autophagy though the exact
mechanism of their actions is under veils. Roles of autophagy and apoptosis other than
their canonical ones are often reported in various pathological processes including
neurodegenerative disorders. We, therefore, in this study investigated the role and
regulation of these two processes. In our preliminary studies, we report a gradual and
significant increase in the levels of both autophagy and apoptosis in cellular and
transgenic animal models of AD, with reduced autophagy flux. Our further investigation
suggests that induction of autophagy in our AD models did not provide any protection
to the cells, however knocking down of Beclin1, a major autophagy protein, led to a
greater viability of neurons under Aβ toxicity. Interestingly, down regulation of Beclin1
led to decline in apoptosis evidently seen in the reduced expressions of its markers.
Taking cue from reports suggesting the role of BH3-only pro-apoptotic protein Puma in
regulating mitophagy and mitochondrial apoptosis, we checked its role in regulating
autophagy in AD. On knocking down Puma, we found a significant reduction in the
initiation of aberrant autophagy as well as increased clearance of cargo in presence of Aβ.
Similar reduced expression of autophagy and apoptosis were observed in rat brains
infused with Aβ in the absence of Puma or Beclin1. We finally demonstrate that this regulation of autophagy and apoptosis could be due to the direct interaction between
the BH3-only proteins Puma and Beclin1, which was significantly elevated when cells
were treated with Aβ. Our study suggests that during AD, in the early phase there is an
activation of aberrant autophagy which may lead to neuron death. It also throws light
upon the role of pro-apoptotic protein Puma in alleviating the anomalous autophagy
flux via a possible crosstalk with Beclin1. Further studies in this field would be helpful to
possibly find out ways in which neuronal viability can be maintained under Aβ stress
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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/2863/1/Thesis_for_Evaluation_Akash_Saha.pdf
Saha, Akash (2021) Role Of Pro-Apoptotic Proteins In Autophagy In Neurodegenerative Diseases. PhD thesis, UNIVERSITY OF CALCUTTA. |
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| Relation |
http://www.eprints.iicb.res.in/2863/
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