Gangliosides, α-Synuclein, and Parkinson's Disease

Abstract

This review addresses the role of α-synuclein (αSyn) in the etiopathology of Parkinson's disease (PD), with emphasis on its interaction with GM1 ganglioside. We begin with a brief review of some of the milestone discoveries that helped to elucidate PD neuropathology, including the fibrous inclusions of Lewy that characterize the degenerating dopaminergic neurons of the substantia nigra and the presence of αSyn as a major constituent of these Lewy bodies and neurites. This enabled Braak et al. to define the progressive nature of PD in developing their staging hypothesis which described the topographically predictable sequence of neuropathological changes giving rise to prodromal nonmotor symptoms that precede the classical motor dysfunctions. We recount recent studies demonstrating strong, specific binding of αSyn to GM1 that serves to inhibit fibril formation and the key role of N-acetylation of αSyn in enhancing GM1 binding and specificity. The consequences of insufficient GM1 are illustrated in a newly presented mouse model of PD based on partial deletion of this ganglioside due to heterologous disruption of B4galnt1 (GM2/GD2 synthase), such mice presenting accurate recapitulation of the PD phenotype. A key feature of these mice was marked elevation of αSyn aggregates which accompanied motor impairment, both aggregates and motor dysfunction being corrected by GM1 replacement therapy. Such therapy was achieved with high dosage of GM1 and more effectively with lower doses of LIGA20, a membrane permeable analog of GM1. The accuracy of this mouse model was emphasized by the finding that various central nervous system and noncentral nervous system tissues from PD patients manifested similar GM1 deficiency as the B4galnt1^+/- mouse. A mechanism is proposed whereby the GM1 deficiency detected in PD patients gives rise to αSyn aggregation and facilitation by the latter in blocking glial cell-derived neurotrophic factor neuroprotection.

Keywords: GM1 deficiency; GM1 functions; GM1 ganglioside; GM1 therapy for PD; Parkinson's disease; mouse model of Parkinson's disease; α-synuclein; α-synuclein conformations; α-synuclein-GM1 association.