Neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Parkinson's and Alzheimer's diseases show early protein aggregation in allocortex compared to neocortex.
• Understanding regional vulnerability is key to explaining disease progression.

Purpose of the Study:

• To model and investigate the differential vulnerability of allocortex and neocortex to proteasome inhibition.
• To explore the molecular mechanisms underlying these regional differences.

Main Methods:

• Microdissection of rat neocortex and allocortex for parallel toxin treatment.
• Assays for proteasome activity, protein ubiquitination, antioxidant levels, and stress-response proteins.
• In vivo studies examining age-related changes in protein and antioxidant levels.

Main Results:

• Allocortical cultures showed higher vulnerability to proteasome inhibitors (MG132, PSI) than neocortical cultures.
• Proteasome impairment was more pronounced in allocortex, indicated by increased ubiquitin-conjugated proteins and reduced proteasome activity.
• Allocortex exhibited compensatory increases in heat shock protein 70, heme oxygenase 1, catalase, and proteasome subunits (PA700, PA28).
• Neocortex had higher basal levels of glutathione and ceruloplasmin; inhibiting these defenses in neocortex increased vulnerability to MG132.
• N-acetyl cysteine rendered allocortex resilient to MG132.
• In vivo, ceruloplasmin levels were higher in neocortex across ages, while PA28 levels increased with age and were higher in allocortex.

Conclusions:

• Allocortex is inherently more susceptible to proteasome dysfunction, a key factor in protein aggregation diseases.
• Differential expression of antioxidant and proteasome machinery contributes to regional vulnerability and compensatory adaptations.
• These findings challenge the view of the telencephalic mantle as a uniform unit and offer insights into the topographic progression of neurodegenerative diseases.