Page 23 - Annual report 2021-22

Annual Report 2021-22 |

Binukumar BK

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Binukumar BK works on the genomics and biology of neurological diseases that affect movement,
learning and memory like dystonia, Wilson’s disease, Parkinson's disease, and Alzheimer’s Disease.
One of the major focuses of the lab is to understand molecular and cellular changes that happen at
the time of neurodegeneration and to develop strategies to delay or prevent the death of neurons.

Most neurodegenerative diseases precipitate and progress with age leading to cognitive impairment
and dementia. Recent evidence suggests Type II diabetes (T2D) to be associated with AD and
dementia. Cyclin dependent kinase 5 (Cdk5), which has a diverse role of action in the normal
functioning of the central nervous system and synaptic plasticity when dysregulated can cause
neurodegeneration and cognitive impairment. Cdk5 expression is high in neurons and pancreas.
Recent reports have highlighted the link between Cdk5 hyperactivation and diabetes-associated
neurodegeneration, but the exact mechanism is still not known which is being investigated by
Binukumar BK’s lab.

His lab demonstrated that Cdk5 and its activators p35 and p25 when overexpressed in HEK293T and
N2A cells, lead to endoplasmic reticulum stress consequently resulting in UPR pathway activation.
Cdk5 phosphorylates threonine 62 of GRP78 causing the activation of the UPR pathway that leads to
activation of the CDK5-GRP78-IRE1-XBP1 arm of UPR. They also showed that Cdk5 is hyperactivated
in the type 2 diabetes (T2D) mouse brain and is implicated in the brain UPR activation and cognitive
impairments in a high-fat diet-induced diabetic mouse model. Antioxidants like NAC (N-acetyl
cysteine) and glutathione could decrease the deregulation of Cdk5 kinase activity and rescue the cells
from UPR mediated ER stress. Moreover, an oral treatment of NAC showed a decrease in the Cdk5
kinase activity in the mouse brain and an ameliorative effect on UPR pathway activation, memory and
learning impairment in T2D mouse model.

To check Cdk5 mediated UPR activation in the T2D brain a diet induced T2D mouse model was
developed. The body weight did not show any marked difference in the NAC treated groups. NAC
treatment did not show any improvement in glucose tolerance and insulin tolerance tests thereby
reflecting that NAC may not be a potent molecule to rescue the disrupted glucose metabolism caused
due to hyperglycemia.

Adipose tissue has a major role to play in the energy homeostasis by secretion of adipokines like
adiponectin, resistin and leptin. A marked significant difference in adiponectin between control and
the high fat group consistent with previous literature that reports a decreased levels of adiponectin in
obese diabetic cases. NAC treatment does not have any notable difference in improving the
adiponectin levels.
Hyperglycemia and hyperinsulinemia and upregulation of Cdk5 and generation of p25 was noted in
the high fat fed group in comparison with the control group of mice. p25 generation leads to
hyperactivation of Cdk5 in the T2D mice brain compared to control mice. Based on these findings the
involvement of Cdk5 in T2D brain was studied using mouse brain hippocampus. It showed the
hyperactivation of Cdk5 activity compared to control group and NAC treatment showed significant