REVIEW
Proteinopathies, a core concept for understanding and ultimately treating degenerative disorders?

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Abstract

The current review covers proteinopathies an umbrella term for neurodegenerative disorders that are characterized by the accumulation of specific proteins within neurons or in the brain parenchyma. Most prevalent examples for typical proteinopathies are Alzheimer's disease and Parkinson's disease. In healthy brain, these proteins are unstructured as a monomer, serving most likely as the physiological form. In a disease condition, the unstructured proteins experience a conformational change leading to small oligomers that eventually will aggregate into higher order structures. Prion disease is an exception within the family of proteinopathies as the aggregated prion protein is highly infectious and can self-aggregate and propagate. Recent reports might implicate a prion-like spread of misfolded proteins in Alzheimer's and Parkinson's disease; however there are evident differences in comparison to prion diseases. As proteinopathies are caused by the aggregation of disease-typical proteins with an ordered structure, active and passive immunization protocols have been used to expose model systems to therapeutic antibodies that bind to the aggregates thereby inhibiting the prolongation into higher ordered fibrils or dissolving the existing fibrillar structure. While most of the immunization treatments have been only carried out in preclinical model systems overexpressing the disease-relevant aggregating protein, other approaches are already in clinical testing. Taking the core concept of proteinopathies with conformationally altered protein aggregates into account, immunization appears to be a very promising therapeutic option for neurodegenerative disorders.

Section snippets

Introduction on the current status of proteinopathies

The present review focuses on proteinopathies of the central nervous system, although the concept also refers to peripheral cells, tissues and organs. The general principle of proteinopathies is that the proteins change their conformation thereby gaining toxic activity or losing the normal function. The most prominent type of a typical proteinopathy is Alzheimer's disease (AD) although many more exist as Parkinson's disease (PD), Lewy body disease, prion disease, tauopathies, amyotrophic

Alzheimer's disease as an example for both amyloidosis and tauopathy

When Alois Alzheimer presented the case of his patient Auguste D. at the Tuebingen meeting of the Southwest German Psychiatrists in 1906, he did not attract much attention or stimulated any discussion in the audience. At this meeting, Alzheimer presented Auguste D.'s symptoms and reported the histopathological features that are now associated with AD: neuron loss, extracellular amyloid plaques and intracellular neurofibrillary tangles (Fig. 1; Table 1) (Alzheimer, 1907). For more than two

Discovery of monoclonal antibodies as tools for therapy

In 1975, Köhler and Milstein established a technique to produce and isolate hybridoma cells producing one type of monoclonal antibody (Kohler and Milstein, 1975). They used a line of myeloma cells that had lost their ability to secrete antibodies, fused these cells with healthy antibody-producing B-cells, and selected for the successfully fused cells. In 1988, Winter and colleagues discovered the techniques to humanize monoclonal antibodies (Riechmann et al., 1988), allowing to develop

Outlook

The pharmaceutical industry is under growing pressure from a range of environmental issues, including major losses of revenue owing to patent expirations, increasingly cost-constrained healthcare systems and more demanding regulatory requirement (Paul et al., 2010). The number of truly innovative best-in-class or first-in-class medicines approved annually by regulatory agencies is flat or declining (Mullard, 2011, Paul et al., 2010). There are some notable exceptions namely therapeutic

Contributors

Stained brain sections were made available by Dr. Gabor Kovacz. Nasrin Saiepour made the pictures.

Role of funding sources

Nothing to state.

Conflict of interest

Nothing to declare.

Acknowldegements

Nothing to state.

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