The role of posttranslational modifications of α-synuclein and LRRK2 in Parkinson's disease: Potential contributions of environmental factors

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD), and the most prevalent movement disorder. PD is characterized by dopaminergic neurodegeneration in the substantia nigra, but its etiology has yet to be established. Among several genetic variants contributing to PD pathogenesis, α-synuclein and leucine-rich repeat kinase (LRRK2) are widely associated with neuropathological phenotypes in familial and sporadic PD. α-Synuclein and LRRK2 found in Lewy bodies, a pathogenic hallmark of PD, are often posttranslationally modified. As posttranslational modifications (PTMs) are key processes in regulating the stability, localization, and function of proteins, PTMs have emerged as important modulators of α-synuclein and LRRK2 pathology. Aberrant PTMs altering phosphorylation, ubiquitination, nitration and truncation of these proteins promote PD pathogenesis, while other PTMs such as sumoylation may be protective. Although the causes of many aberrant PTMs are unknown, environmental risk factors may contribute to their aberrancy. Environmental toxicants such as rotenone and paraquat have been shown to interact with these proteins and promote their abnormal PTMs. Notably, manganese (Mn) exposure leads to a PD-like neurological disorder referred to as manganism-and induces pathogenic PTMs of α-synuclein and LRRK2. In this review, we highlight the role of PTMs of α-synuclein and LRRK2 in PD pathogenesis and discuss the impact of environmental risk factors on their aberrancy.

Keywords: LRRK2; Manganese; Parkinson's disease; Posttranslational modifications; α-Synuclein.

Figure 1.

Schematic diagram of the protein domains and posttranslational modification sites of α-synuclein (A) and LRRK2 (B). Pathogenic mutations are italicized, whereas posttranslational modification sites are in bold. (A) The domains of α-synuclein are N-terminal amphiphatic (AMP), non-amyloid component (NAC) and acidic (ACID) domains. (B) The domains of LRRK2 are armadillo (ARM), ankyrin (ANK), leucine-rich repeats (LRR), Ras of complex (ROC), C-terminal of ROC (COR), kinase (KIN) and WD40. Posttranslational modification sites are depicted in red for phosphorylation and blue for ubiquitination. Other posttranslational modifications in α-synuclein are labelled (^#) for nitration and (^@) for acetylation. Truncation of α-synuclein occurs in its C-terminal (ACID) domain. Autophosphorylation sites in LRRK2 are underlined.

Figure 2.

Schematic representation of the potential interplay of genetic and environmental factors influencing aberrant posttranslational modification of LRRK2 and α-synuclein in PD.