Exploring α-Syn's Functions Through Ablation Models: Physiological and Pathological Implications

Abstract

A significant advancement in neurodegenerative research was the discovery that α-synuclein (α-Syn/SNCA) plays a part in the pathophysiology of Parkinson's disease (PD). Decades later, the protein's significant impacts on various brain disorders are still being extensively explored. In disease conditions, α-Syn misfolds and forms abnormal aggregates that accumulate in neurons, thus triggering various organellar dysfunctions and ultimately neurodegeneration. These misfolded forms are highly heterogeneous and vary significantly among different synucleinopathies, such as PD, Multiple System Atrophy, or Dementia with Lewy bodies. Though initially believed to be exclusively localized in the brain, numerous pieces of evidence suggest that α-Syn functions transcend the central nervous system, with roles in peripheral functions, such as modulation of immune responses, hematopoiesis, and gastrointestinal regulation. Here, we aim to provide a detailed compilation of cellular functions and pathological phenotypes that are altered upon attenuation of α-Syn function in vitro and in vivo and explore the effects of SNCA gene silencing in healthy and disease states using cellular and animal models.

Keywords: SNCA; α-Syn; Ablation models; Parkinson's disease; Synuclein.

Fig. 1

Structural organization of α-Syn. In the cytosol, α-Syn exists as an unfolded protein. It has three major domains: NTD, NAC domain and CTD which facilitate lipid binding and secondary folding

Fig. 2

Role of α-Syn in vesicular mobility and neurotransmitter release. a In SNCA WT expressing neurons, monomeric α-Syn binds to RP vesicles and limits their conversion to RRP, thereby regulating neurotransmission. b However, in SNCA KO neuron, a higher conversion of RP to RRP and higher dopamine levels in the synaptic cleft are observed

Fig. 3

Role of α-Syn in T-lymphocyte maturation. a In Snca WT animals, maturation of T cell occurs in a highly ordered manner, producing the single positive mature T-lymphocytes of either CD4+ or CD8+ lineage. b On the other hand, Snca KO animals exhibit an overall reduction in mature lymphocyte count, with some of the surviving cytotoxic T-lymphocyte showing aberrant early activation markers on its cell surface

Fig. 4

Role of α-Syn in MPP+ mediated toxicity. a SNCA WT expressing dopaminergic neurons are highly sensitive to MPP+. MPP+ enters the neuron via DAT and cause ROS generation through mitochondrial dysfunction. This is believed to trigger α-Syn misfolding and ultimately neurodegeneration. b The SNCA KO dopamine neurons are resilient to MPP+ toxicity. The absence of α-Syn facilitates an increase in β-Syn and VMAT2, which shows neuroprotective action and prevents MPP+ from compromising mitochondrial function