α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies

Abstract

Alterations in α-synuclein dosage lead to familial Parkinson's disease (PD), and its accumulation results in synucleinopathies that include PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Furthermore, α-synuclein contributes to the fibrilization of amyloid-b and tau, two key proteins in Alzheimer's disease, which suggests a central role for α-synuclein toxicity in neurodegeneration. Recent studies of factors contributing to α-synuclein toxicity and its disruption of downstream cellular pathways have expanded our understanding of disease pathogenesis in synucleinopathies. In this Review, we discuss these emerging themes, including the contributions of aging, selective vulnerability and non-cell-autonomous factors such as α-synuclein cell-to-cell propagation and neuroinflammation. Finally, we summarize recent efforts toward the development of targeted therapies for PD and related synucleinopathies.

Figure 1

Pathways implicated in α-synuclein toxicity. (a–c) Organelle dysfunction (a, purple boxes), defects in inter-organelle contacts (b, blue box) and dysfunctional organelle dynamics (c, green box) have all been implicated in α-synuclein toxicity.

Figure 2

Therapeutically targeting α-synuclein toxicity. Various pathways have been manipulated to decrease α-synuclein toxicity, largely in mouse models of α-synuclein toxicity. These include (i) reducing α-synuclein synthesis with siRNAs, (ii) increasing α-synuclein degradation, (iii) reducing α-synuclein aggregation, (iv) blocking α-synuclein propagation and (v) active immunization of α-synuclein. Drug development to increase lysosomal activity via glucocerebrosidase (GCase) to accelerate α-synuclein degradation, as well as clinical trials using both passive and active immunization against α-synuclein, are currently under way.