Protein Misfolding, Signaling Abnormalities and Altered Fast Axonal Transport: Implications for Alzheimer and Prion Diseases.

Emiliano Zamponi,Gustavo F Pigino

doi:10.3389/fncel.2019.00350

Abstract

Histopathological studies revealed that progressive neuropathies including Alzheimer, and Prion diseases among others, include accumulations of misfolded proteins intracellularly, extracellularly, or both. Experimental evidence suggests that among the accumulated misfolded proteins, small soluble oligomeric conformers represent the most neurotoxic species. Concomitant phenomena shared by different protein misfolding diseases includes alterations in phosphorylation-based signaling pathways synaptic dysfunction, and axonal pathology, but mechanisms linking these pathogenic features to aggregated neuropathogenic proteins remain unknown. Relevant to this issue, results from recent work revealed inhibition of fast axonal transport (AT) as a novel toxic effect elicited by oligomeric forms of amyloid beta and cellular prion protein PrPC, signature pathological proteins associated with Alzheimer and Prion diseases, respectively. Interestingly, the toxic effect of these oligomers was fully prevented by pharmacological inhibitors of casein kinase 2 (CK2), a remarkable discovery with major implications for the development of pharmacological target-driven therapeutic intervention for Alzheimer and Prion diseases.

Highlights

Adult-onset misfolding diseases are among the most challenging disorders faced by modern molecular medicine
For many decades the research on pathological mechanisms associated to adult onset neurological disorders such as AD and other aggregopathies, was focused almost exclusively on preventing neuronal cell death
Cardinal research programs aimed to genetically prove the direct involvement of apoptosis, a pathological component of AD, PD, prion diseases (PrDs), and amyotrophic lateral sclerosis (ALS), determined that apoptosis plays an important role in these diseases, preserving affected neurons did not prevent the clinical symptoms or synaptic dysfunction and loss (Chiesa et al, 2005; Gould et al, 2006)

Summary

Introduction

Adult-onset misfolding diseases are among the most challenging disorders faced by modern molecular medicine. Cumulative evidence indicates that deficits in neuronal connectivity associated with synaptic disfunction and axonal degeneration, rather than the loss of specific population of vulnerable neurons, underlies the clinical manifestation of each disease (Chiesa et al, 2005; Brady and Morfini, 2010; Coleman, 2011).

Results

Conclusion