Abstract
The key aspect of the classification of neurodegenerative diseases is the histopathological detection of certain proteins in the brain. The various disease entities are distinguished with respect to the type of detected protein and with respect to the configuration and localization of the corresponding protein aggregates. Aggregates of alpha-synuclein (ASYN) are the defining hallmark of several neurodegenerative disorders termed synucleinopathies. The most well-known diseases in this spectrum are Parkinson's disease (PD) with neuronal detection of Lewy bodies, dementia with Lewy bodies (DLB), with additional detection of beta-amyloid and multiple system atrophy (MSA), where ASYN aggregates are found in glia cells in the form of Papp-Lantos inclusions. ASYN has been identified as a key target for the development of therapeutic approaches to synucleinopathies given its central role in the pathophysiology of these diseases. Current treatment strategies can be roughly classified into six groups: 1) lowering ASYN expression (antisense therapy), 2) inhibition of formation of toxic ASYN aggregates (aggregation inhibitors, chelators), 3) dissolving or removal of intracellular or extracellular toxic AYSN aggregates (active and passive immunotherapy, aggregation inhibitors), 4) enhancement of cellular clearance mechanisms (autophagy, lysosomal microphagy) for removal of toxic forms of alpha-synuclein, 5) modulation of neuroinflammatory processes and 6) neuroprotective strategies. This article summarizes the current therapeutic approaches and sheds light on promising future treatment approaches.