Protein Degradation Pathways in ParkinsonĀ“s Disease and Neurodegeneration

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Background

Neurodegenerative diseases of aging, such as ParkinsonĀ“s disease (PD), are an increasing social and health burden in modern society, for which no disease-modifying therapy is currently available. These disorders share neuropathological features with proteinaceous inclusions detectable at autopsy. The different diseases present a characteristic protein that aggregates in these inclusions. In ParkinsonĀ“s disease, Lewy bodies and neurites are observed in several brain areas and mainly consist of aggregated alpha-synuclein. Intense research efforts have focused on understanding the role of these neuropathological features in the onset and progression of neurodegeneration. While a causal relationship is still spurious, it is becoming evident that the cellular machineries responsible for the clearance of unwanted protein material are affected in patient brains, which can be recapitulated in cellular and animal disease models. For example, alterations in the autophagy-lysosome pathway are observed in the brain of PD patients and deficits in this process in experimental models are capable of causing neurodegeneration and neuropathology. Furthermore, gene mutations and alterations linked to familial PD cause defects in autophagy, suggesting that failure of protein clearance could underlie early, causal events in the disease process.

The translational potential of this knowledge has been widely pursued, e.g. autophagy activation has been tested as an experimental therapeutic strategy to prevent or slow down neurodegeneration. However, increasing evidence indicates that a much more complex and subtle control of autophagy will be required. Indeed, specific parts of the autophagy pathway are altered in specific conditions, and thus non-selective upstream activation will not be beneficial when downstream steps do not function correctly. More research is needed to clarify what, where and when protein clearance becomes faulty. Crucial insights may come from genetic determinants, indicating etiologically relevant mechanisms that should be explored in detail. This will allow to select appropriate targets for genetic or pharmacological modulation in order to develop potential disease-modifying therapies.

In addition, the role of the ubiquitin-proteasome system as a parallel and/or alternative system to clear toxic proteins is also being investigated, although the balance between the two processes is difficult to dissect experimentally. As an example, it is postulated that alpha-synuclein is degraded by the proteasome in physiologic conditions and by autophagy in pathological forms. However, this relationship appears more complicated as dynamic regulations likely occur during the pathologic process.

In this Research Topic, we aim at research articles and reviews that focus on the link between protein degradation processes and neurodegenerative diseases. This includes both translational strategies targeting protein degradation pathways and research on the fundamental molecular mechanisms underlying protein degradation processes (e.g. autophagy and lysosomal pathways). This will provide better insight in the early phases of neurodegenerative diseases, and thus contribute to the ultimate goal of finding a disease-modifying therapy.

Keywords: Autophagy, neuropathology, alpha-synuclein, ParkinsonĀ“s disease, protein clearance

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