Protein Misfolding and Accumulation as Root Cause in Neurodegeneration

The current concept that accumulation and aggregation of misfolded proteins could represent a basic requirement for the neurodegenerative processes, has raised the attention to the efficiency of cell clearance machinery in influencing neuronal protein homeostasis. Indeed, although multifactorial etiology of Alzheimer’s disease (AD) and Parkinson disease (PD) progression, molecular events activated by environmental conditions and epigenetic mechanisms are strongly associated to oxidative stress and inflammatory damage that in turn seems to find a common origin in the anomalous accumulation of misfolded proteins. Amyloid-β and tau for AD and alpha-synuclein for PD have been proposed as the central and most specific factors implied in the pathogenesis of these syndromes, which, as a consequence, have been classified as a proteinopathies. Aggregated structures result inappropriate for proteasomal degradation and justify recent studies highlighting the importance of autophagy, a lysosomal degradation pathway, in misfolded proteins degradation in neurons. Therefore, the poor efficiency of autophagy might be a primum movens in the physiopathology of neurodegenerative diseases. When other pathogenic mechanisms arise, they determine a compensatory induction of autophagy pathways; if this activation is not appropriate to reestablish neuronal homeostasis and prevent accumulation of neurotoxic products, the neurodegenerative process develops. According to a recent theory regarding cell aging, a major responsible for the death of neurons, would be the neurotoxic effect of aberrant proteins and mitochondria, accumulating within senescent cells as a consequence of an agerelated progressive dysfunction of different catabolic pathways.