“Janus-Faced” α-Synuclein: Role in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a pathological condition characterized by the aggregation and the resultant presence of intraneuronal inclusions termed Lewy bodies (LBs) and Lewy neurites which are mainly composed of fibrillar α-synuclein (α-syn) protein. Pathogenic aggregation of α-syn is identified as the major cause of LBs deposition. Several mutations in α-syn showing varied aggregation kinetics in comparison to the wild type (WT) α-syn are reported in PD (A30P, E46K, H 50Q, G51D, A53E, and A53T). Also, the cell-to-cell spread of pathological α-syn plays a significant role in PD development. Interestingly, it has also been suggested that the pathology of PD may begin in the gastrointestinal tract and spread via the vagus nerve (VN) to brain proposing the gut–brain axis of α-syn pathology in PD. Despite multiple efforts, the behavior and functions of this protein in normal and pathological states (specifically in PD) is far from understood. Furthermore, the etiological factors responsible for triggering aggregation of this protein remain elusive. This review is an attempt to collate and present latest information on α-syn in relation to its structure, biochemistry and biophysics of aggregation in PD. Current advances in therapeutic efforts toward clearing the pathogenic α-syn via autophagy/lysosomal flux are also reviewed and reported.

How oxidized EGCG remodels α-synuclein fibrils into non-toxic aggregates: insights from computational simulations

“…The NAC domain is believed to be responsible for α-syn aggregation, leading to the formation of β-sheet-rich amyloid fibrils. 4…”

“…It results in the loss of dopaminergic neurons in the substantia nigra pars compacta. 4,5 Besides PD, there is a group of disorders characterized by the accumulation of inclusions enriched in a-syn called synucleinopathies, including Lewy body dementia (LBD), multiple system atrophy (MSA), and pure autonomic failure (PAF). 6 Due to the central role of a-syn in the pathology of PD and other forms of synucleinopathies, the lack of an early and definitive antemortem diagnosis for synucleinopathies, and effective treatment, numerous studies have been focused on targeting a-syn for diagnosis and therapeutics.…”

“…The NAC domain is believed to be responsible for a-syn aggregation, leading to the formation of b-sheet-rich amyloid fibrils. 4 Tuttle et al (2016) elucidated a structure of the synthetic a-syn fibril obtained from recombinantly expressed a-syn in vitro, which induced a robust PD-like pathology in primary neuronal culture. 10 This a-syn fibril, whose 3D structure was determined by solid-state nuclear magnetic resonance (SS-NMR) spectroscopy, exhibits a unique conformation in which the core residues are arranged in parallel, in-register b-sheets with an especially compact Greek key topology.…”

Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson’s Disease Models In Vivo and In Vitro

“…The main function of α-synuclein may be to regulate the activity of synaptic vesicles, the release of neurotransmitters, and the recycling of synaptic vesicles. In addition, studies have shown that α-synuclein is involved in neuronal Golgi and vesicle transport, membrane structure regulation, lipid metabolism, mitochondrial fusion, DNA repair, and cognitive functions [4]. The structure of α-synuclein is unstable, and the αhelix conformer is easily replaced by a β-sheet.…”

Focus on the Small GTPase Rab1: A Key Player in the Pathogenesis of Parkinson’s Disease

“…Multiple mutations present in family members with PD are known, including autosomal dominant ( SNCA , LRRK2 , VPS35 ) and recessive ( PARK2 , PINK1 , DJ-1 ) forms [ 25 ], although many additional risky loci have been identified [ 26 , 27 ]. The overexpression (duplication or triplication) or mutation of the SNCA gene is known to be a cause of familial PD [ 25 , 28 , 29 ]. Most SNCA point mutations are associated with the early onset of disease.…”