Journal de la maladie d'Alzheimer et du parkinsonisme

Abstrait

Stochastic Considerations into the Origins of Sporadic Adult Onset Neurodegenerative Disorders

Peter K Panegyres

Objective: Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia and other neurodegenerative disorders share common properties including protein interactions, cellular reactions, inflammatory process involving microglia, prion-like propagation in a neuronal network, synaptic and neuronal loss. The misfolding and aggregation of specific proteins seems to be an early and obligatory event of which the antecedents are unknown.
Methods: Studies in prion diseases and AD implicate the conversion of disease-specific proteins into aggregates of prion-like beta-sheets. Most of the common neurodegenerative disorders are sporadic, with <5% resulting from genetic mutations. This work aims to explain the mechanisms by which most neurodegenerative disorders are sporadic.
Results: It is posited that variation in protein sequences may be caused by stochastic processes at a DNA, mRNA or protein level. This sequence variation is resistant to the neuron’s normal control mechanisms and results in disease through protein misfolding, over-proliferation and spread. If not handled by the cell’s normal mechanisms, such as phagosome function, the process might result in disease.
Conclusion: The association with neurodegenerative disorders with age correlates with failure of the cell’s normal mechanisms, such as autophagosomes and agressomes, to deal with this sequence variation. These considerations raise evolutionary questions as to the origins of neurodegenerative disorders in humans.