Novel approaches to counter protein aggregation pathology in Parkinson's disease

Abstract

The primary neuropathological characteristics of the Parkinsonian brain are the loss of nigral dopamine neurons and the aggregation of alpha synuclein protein. Efforts to development potentially disease-modifying treatments have largely focused on correcting these aspects of the condition. In the last decade treatments targeting protein aggregation have entered the clinical pipeline. In this chapter we provide an overview of ongoing clinical trial programs for different therapies attempting to reduce protein aggregation pathology in Parkinson's disease. We will also briefly consider various novel approaches being proposed-and being developed preclinically-to inhibit/reduce aggregated protein pathology in Parkinson's.

Keywords: Aggregation; Alpha synuclein; Immunotherapy; Lewy body; Neurodegeneration.

Figure 1

A cartoon representation illustrating how immunotherapy and small molecule inhibitors are being tested in PD. Monomeric α-syn is produced (1.), but in PD the protein aggregates for unknown reasons (2.). This oligomerisation is believed to lead to pathology, such as the formation of Lewy bodies (3.). Aggregated α-syn is also released extraneuronally (4.). Immunotherapies (such as Prasinezumab, BIIB054, and PD01A) targeting extracellular α-syn oligomers (5.) are being clinically evaluated to determine if they can slow the spread of the condition. In addition, small molecule inhibitors of α-syn aggregation (such as Anle138b & ENT01) - which are not necessarily limited to the extracellular space - are able to bind to α-syn oligomers (6.) and disaggregate them (7.), reducing levels of both extra- and intracellular oligomeric α-syn.

Figure 2.

Lysosomal and autophagic clearance of waste is a necessary cellular function. It begins with the production and lysosomal uptake of digestive enzymes (1.), such as Glucocerebrosidase (GCase). In parallel, waste is collected in autophagosome vesicles (2.), which then dock and fuse with lysosomes (3.). After digestion, the contents of the vesicle can be exocytosed (4.) or recycled. The lysosomal disfunction observed in PD may involve faulty or reduced digestive enzyme activity (for example GCase), which might remain attached to the endoplasmic reticulum (ER) or fail to correctly break down proteins in the lysosome, resulting in incomplete digestion of vesicular contents (5.). This situation may cause cellular stress, leading to pathology. Intracellular stress may also be induced by the accumulation of un-recycled waste (6.), which could also lead to PD pathology. Lysosomal therapies being clinically tested for PD are primarily focused on enhancing GCase activity (such as Ambroxol, LTI-291, and PR001), while autophagy inducers (including Nilotinib, K0706, and RTB101) are being evaluated for their ability to increase waste disposal and reduce cellular stress.