Page 24 - Annual report 2021-22

Annual Report 2021-22 |

decrease in the Cdk5/p25 activity in high fat group, compared to the respective control group.
Previously, it has been shown that serine 396 in the Tau protein is a potential Cdk5 phosphorylation
site. Phospho-tau (ser396) levels are significantly high in T2D mouse brain compared to control. These
changes, however, were significantly attenuated by NAC treatment, in some cases almost to baseline
levels (p < 0.05). Previous studies report a deceased glutathione (GSH) synthesis and concentration in
T2D erythrocytes. A diminished concentration of GSH was shown in the T2D brain hippocampus 7
compared to the control group. Treatment with NAC showed restoration in the GSH levels.

Unfolded Protein Response (UPR) activation in type II diabetes brains via the IRE1-JNK pathway was
seen. The upregulation of heat shock proteins namely GRP78 and GRP94 in T2D brain was shown. The
activation of the IRE1 pathway, at protein and mRNA level, of UPR signalling in the high-fat brain
hippocampus was seen. A significantly decreased expression of GRP78 and IRE1 in NAC treated
diabetic mice was seen. Consequently, activated IRE1 cleaves XBP-1 and an elevated mRNA expression
of the spliced form of XBP-1 was noted with respect to total Xbp-1 through real-time PCR experiment.
Upregulated expression of both JNK-1, another downstream target of IRE-1, and p-SAPK/JNK in the
high fat group was observed and subsequent NAC treatment reduced their expression levels. A
significant decrease in GFAP and p-tau in case of NAC treated mice with 100 mg/kg dose indicated
rescue in neuroinflammation that was impaired in diabetic group.

The activation of the other two arms of UPR signalling - ATF6 and PERK- were checked in the diabetic
mouse brain hippocampus. Though an increase in ATF6 protein level was observed in the diabetic
group, a significantly consistent upregulation was not found among the animals of the diabetic high
fat groups. There was no significant change in the protein expression level of PERK and its downstream
targets p-PERK, EIF 2a and GADD34. Thus, it was concluded that the UPR induction is through the IRE1-
JNK1-CHOP pathway.

Another focus area of his lab is on identifying modifiers of neurological diseases for preventive and
prognostic interventions. In this direction, neuro Wilson's disease (WD) modelling is under progress.
His lab established a consortium entitled “Indian Collaborative Research Network on Wilson's Disease”
(iCROWD) Understanding molecular genetics towards better diagnosis and therapy” as a primary
forum and network to this end. A pilot network of over 45 clinicians from over 25 centres across the
country have already been established. WD is a rare disease that shows an autosomal recessive
inheritance pattern. Copper accumulation in the body is the major factor that contributes to the
disease associated symptoms. Liver dysfunction and neurological symptoms are mostly seen and may
appear separately with some patients developing only the neurological symptoms (known as neuro
WD) and vice versa. To achieve the disease modeling for neuro WD, 195 clinically Wilsons disease
(WD) patients from different parts of India were enrolled. DNA isolation and ATP7B (Wilson gene)
sequencing was completed for these patients. 2 neuro WD specific patient PBMC and normal PBMC
were successfully isolated and cultured. Generation of normal and neuro WD specific iPSC is in
progress.
In collaboration with Sridhar Sivasubbu, he was also involved in the genomic testing for over 1200
samples collected from individuals suffering from/carrier for Wilson’s disease.