Nuclear accumulation of GAPDH, GluA2 and p53 in post-mortem substantia nigral region of patients with Parkinson's disease

Neurosci Lett. 2020 Jan 18;716:134641. doi: 10.1016/j.neulet.2019.134641. Epub 2019 Nov 20.

Abstract

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been well documented in glycolytic pathway. Independent of this, it has various other functions including stimulator of programmed cell death. Reports suggest that glutamate receptor AMPA type-2 subunit (GluA2) forms protein complex with GAPDH and internalized during excitotoxicity. Further, nuclear accumulation of GluA2 and GAPDH have been studied in neurological disorders like epilepsy and multiple sclerosis, and disruption of this complex rescued neurological symptoms such as astrogliosis, AMPA mediated excitotoxicity and p53 phosphorylation. On the other hand, study on ischemic rat model showed that nucleus translocated GAPDH binds with p53 leading to apoptosis. However, the molecular events underlying these processes remained to be established in Parkinson's disease (PD). The present study focused on investigating the levels of GAPDH, GluA2 and p53 in the nuclear fraction (NF) and total homogenate (TH) of substantia nigral (SN) region obtained from post-mortem PD brains and their age-matched controls. The level of caspase 3, an apoptotic marker and mediator for p53 induced cell death was also measured. A significant increase in nuclear GAPDH, GluA2 and p53 were observed in PD SN region, compared to the controls. Similarly, increased caspase 3 level was observed in PD SN region. Data obtained from the present study suggest that nuclear accumulation of GAPDH, GluA2 and p53 plays a key role in the pathophysiology of neuronal cell death in PD. Thus decreasing nuclear translocation of these death pro-death signaling markers may attenuate neurodegeneration that aids in the development of potential therapeutic targets in the management of PD.

Keywords: Death signals; Nuclear translocation; Parkinson’s disease; Post-mortem brain; Substantia nigra.

MeSH terms

  • Aged
  • Autopsy
  • Cell Nucleus / metabolism
  • Female
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism*
  • Humans
  • Male
  • Parkinson Disease / metabolism
  • Parkinson Disease / physiopathology*
  • Receptors, AMPA / metabolism*
  • Substantia Nigra / metabolism
  • Substantia Nigra / physiopathology*
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Receptors, AMPA
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • GAPDH protein, human
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
  • glutamate receptor ionotropic, AMPA 2