Blocking dPerk in the intestine suppresses neurodegeneration in a Drosophila model of Parkinson's disease.
Rebeka PopovicAmrita MukherjeeNuno Santos LealLydia MorrisYizhou YuSamantha H Y LohLuis Miguel MartinsPublished in: Cell death & disease (2023)
Parkinson's disease (PD) is characterised by selective death of dopaminergic (DA) neurons in the midbrain and motor function impairment. Gastrointestinal issues often precede motor deficits in PD, indicating that the gut-brain axis is involved in the pathogenesis of this disease. The features of PD include both mitochondrial dysfunction and activation of the unfolded protein response (UPR) in the endoplasmic reticulum (ER). PINK1 is a mitochondrial kinase involved in the recycling of defective mitochondria, and PINK1 mutations cause early-onset PD. Like PD patients, pink1 mutant Drosophila show degeneration of DA neurons and intestinal dysfunction. These mutant flies also lack vital proteins due to sustained activation of the kinase R-like endoplasmic reticulum kinase (dPerk), a kinase that induces the UPR. Here, we investigated the role of dPerk in intestinal dysfunction. We showed that intestinal expression of dPerk impairs mitochondrial function, induces cell death, and decreases lifespan. We found that suppressing dPerk in the intestine of pink1-mutant flies rescues intestinal cell death and is neuroprotective. We conclude that in a fly model of PD, blocking gut-brain transmission of UPR-mediated toxicity, is neuroprotective.
Keyphrases
- endoplasmic reticulum
- cell death
- early onset
- oxidative stress
- cerebral ischemia
- protein kinase
- tyrosine kinase
- traumatic brain injury
- end stage renal disease
- spinal cord
- ejection fraction
- wild type
- poor prognosis
- resting state
- spinal cord injury
- mass spectrometry
- brain injury
- mouse model
- binding protein
- subarachnoid hemorrhage
- cell cycle arrest
- atomic force microscopy
- endoplasmic reticulum stress
- estrogen receptor
- patient reported outcomes
- patient reported
- pi k akt
- breast cancer cells
- small molecule
- high speed