Limelight on Alpha-Synuclein: Pathological and Mechanistic Implications in Neurodegeneration

Abstract

The pathogenesis of many neurodegenerative disorders arises in association with the misfolding and accumulation of a wide variety of proteins. Much emphasis has been placed on understanding the nature of these protein accumulations, including their composition, the process by which they are formed and the physiological impact they impose at cellular and, ultimately, organismal levels. Alpha-synuclein (ASYN) is the major component of protein inclusions known as Lewy bodies and Lewy neurites, which are the typical pathological hallmarks in disorders referred to as synucleinopathies. In addition, mutations or multiplications in the gene encoding for ASYN have also been shown to cause familial cases of PD, the most common synucleinopathy. Although the precise function of ASYN remains unclear, it appears to be involved in a vast array of cellular processes. Here, we review, in depth, a spectrum of cellular and molecular mechanisms that have been implicated in synucleinopathies. Importantly, detailed understanding of the biology/pathobiology of ASYN may enable the development of novel avenues for diagnosis and/or therapeutic intervention in synucleinopathies.The initial implication of alpha-synuclein (ASYN) in neurodegeneration arose with the identification of its presence in amyloid plaques of Alzheimer's disease (AD) patients [1]. Though ASYN was discovered half a decade prior, in the electric organ of Torpedo californica, and initially named synuclein for its ostensibly restricted cellular localizations, within synaptic nerve terminals and within the nuclear envelope [2], 1 Equal contribution.

Structure, function and toxicity of alpha‐synuclein: the Bermuda triangle in synucleinopathies

“…a-syn was also shown to interact with histones and, despite controversial findings, a-syn may affect histone function via acetylation-deacetylation cycles, a process that might be strongly dependent on a-syn levels (Kontopoulos et al 2006;Liu et al 2011). For a detailed description of the role of a-syn in the nucleus we forward the reader to another review more focused on the topic (Wales et al 2013).…”

DJ-1 (Park7) affects the gut microbiome, metabolites and development of Innate Lymphoid cells (ILCs)

“…Unwanted activation of the innate immune system from small intestinal bacterial overgrowth leads to increased intestinal permeability and may cause systemic inflammation (41). In the same perspective, unwanted activation of enteric neurons and enteric glial cells could follow the initiation of α-Syn accumulation and misfolding in the gut and the brain (51). In addition to the innate immune system, the adaptive immune system could also be affected and changed by bacterial proteins cross-reacting with host antigens and could lead to severe inflammation of the host tissues (52).…”

Progress toward an integrated understanding of Parkinson’s disease

“…α-Syn was first described as a member of the synuclein family, which is associated with the synapse and the nucleus 85 . While studies on the physiological function of α-Syn suggest that it may play a role in synaptic transmission 86 and aid in curving cellular membranes 87 , less is known regarding the mechanism(s) through which its gain-of-function causes neurodegeneration. Thus, one aspect of α-Syn research has focused on understanding how this protein causes toxicity within the cell.…”