Protein Misfolding in Neurodegenerative Brain Diseases: The Key Questions
Prions

Protein Misfolding in Neurodegenerative Brain Diseases: The Key Questions

By March 30, 2018 No Comments

Originally Posted on Journal of Neurology & Translational Neuroscience | 19 August 2013

Dr Soto, expert on Neurodegenerative Brain Diseases

 

Neurodegenerative brain diseases are chronic and often fatal illnesses that affect the most precious qualities of human beings. This group of disorders include highly prevalent diseases such as Alzheimer’s and Parkinson’s, and other rarer as Hungtinton’s disease, spinocerebellar ataxia, prion diseases (also called transmissible spongiform encephalopathies), and amyotrophic lateral sclerosis. Despite the diversity in clinical manifestation, neurodegenerative diseases share many common features including their relationship to aging, the progressive and chronic nature of the disease, the extensive, but localized lost of neurons and synaptic abnormalities and the presence of cerebral deposits of misfolded protein aggregates.

Research over the past 20 years has provided compelling evidence for a key role of these aggregates as the culprits of neurodegeneration. Each neurodegenerative brain disease is associated with abnormalities in the folding, leading to formation of oligomers and large aggregates composed of a different protein. In this article, I outline the main pending questions related to the involvement of misfolded protein aggregates in neurodegenerative brain diseases.

Are misfolded aggregates the cause of neurodegenerative brain diseases?

Despite compelling evidence from genetic, biochemical and neuropathological analysis as well as studies with animal models, it still remains not completely proven that accumulation of misfolded protein aggregates is the underlying cause of the disease. It is likely that the definitive proof will only be obtained if the disease can be successfully treated or prevented by elimination of misfolded aggregates.

What is the identity and structure of the toxic form of misfolded aggregates?

The process of protein misfolding and aggregation results in the formation of a continuum of particles of different size and structure, ranging from dimmers to very large fibrils. The majority of the evidence points that small, soluble oligomers are the most neurotoxic species in the brain. However, it is likely that many different aggregates may be toxic, perhaps by distinct mechanisms. Moreover, it seems clear that the various particles are in a dynamic equilibrium among each other, further complicating the study of their specific properties. The heterogeneity, interconversion, insolubility and non-crystalline nature of misfolded aggregates impose enormous complications for elucidation of the atomic-resolution structure of these molecules. Nevertheless, much progress has been done in recent years, especially using short peptide models of protein aggregates.

How misfolded aggregates induce neuronal damage?

It was initially thought that neuronal apoptosis was the most important problem in neurodegeneration, however recent evidence from different diseases, suggest that extensive neuronal death may not be the initial cause of the disease. Indeed, clinical symptoms have been clearly described before significant neuronal loss and a better temporal and topographic correlation is found with synaptic dysfunction. Although the mechanism of neurotoxicity is a topic extensively studied and many different hypotheses have been proposed, it is still unclear which of the different models operates in vivo in the human brain. Some of the pathways proposed include : (i) activation of signal transduction pathways leading to neuronal dysfunction; (ii) recruitment of cellular factors essential for neuronal functioning; (iii) membrane disruption and depolarization mediated by pore formation; (iv) impairment of the protein homeostasis machinery in the cell; (v) extensive oxidative and endoplasmic reticulum stress; (vi) induction of mitochondrial dysfunction; (vii) triggering a chronic inflammatory reaction in the brain.

 

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