Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

Abstract

α-synuclein (α-syn) is an intrinsically disordered protein abundant in the central nervous system. Physiologically, the protein regulates vesicle trafficking and neurotransmitter release in the presynaptic terminals. Pathologies related to misfolding and aggregation of α-syn are referred to as α-synucleinopathies, and they constitute a frequent cause of neurodegeneration. The most common α-synucleinopathy, Parkinson’s disease (PD), is caused by abnormal accumulation of α-syn in the dopaminergic neurons of the midbrain. This results in protein overload, activation of endoplasmic reticulum (ER) stress, and, ultimately, neural cell apoptosis and neurodegeneration. To date, the available treatment options for PD are only symptomatic and rely on dopamine replacement therapy or palliative surgery. As the prevalence of PD has skyrocketed in recent years, there is a pending issue for development of new disease-modifying strategies. These include anti-aggregative agents that target α-syn directly (gene therapy, small molecules and immunization), indirectly (modulators of ER stress, oxidative stress and clearance pathways) or combine both actions (natural compounds). Herein, we provide an overview on the characteristic features of the structure and pathogenic mechanisms of α-syn that could be targeted with novel molecular-based therapies.

Alpha-Synuclein Contribution to Neuronal and Glial Damage in Parkinson’s Disease

“…In contrast, in familial cases with specific mutations underlying the disease, gene therapy seems to be the most reasonable. However, considering the multifaceted molecular changes in PD pathogenesis and uncertainties about the direct role of αSyn, combination therapy addressing various molecular pathways emerges as the most promising approach for the future [ 344 ]. Until then, however, the efficacy and safety of such approaches will have to be thoroughly evaluated in large-scale trials to bring the greatest benefit to patients with the fewest side effects.…”