SNCA encodes α-synuclein, which is predominantly a synaptic protein that is encoded by the SNCA gene. Missense mutations as well as mutations leading to duplications and triplications of SNCA have been identified in autosomal dominant PD ^{[1][2][3][4][5][6]}[85,86,87,88,89,90]. The discoveries that increasing the gene dosage of SNCA by 2- to 3-fold can cause PD ^[5][89] is significant for idiopathic PD, because it indicates that elevated wild-type (WT) α-synuclein alone is sufficient to cause the disease. In addition to familial PD, α-synuclein aggregation is also detected in the Lewy bodies of idiopathic PD ^[7][91]. Lewy bodies are intracellular inclusions that consist of aggregated α-synuclein, and more recently, they have also been reported to contain lipids and organelles such as mitochondria ^[8][92]. Pathogenic mechanisms associated with α-synuclein mutations range from impairing protein degradation pathways (autophagy and ubiquitin proteasomal system), mitochondrial dysfunction, oxidative stress, synaptic dysfunction, and neuroinflammation ^[9][93]. There has also been a significant interest in the spread of α-synuclein pathology from one cell to another in a prion-like fashion ^[10][75] and Mn has been demonstrated to enhance this transmission ^[11][74].

Mn can bind to α-synuclein via three residues in the C-terminal domain: Asp-121, Asn-122, and Glu-123 ^[12][94]. Although this is a low-affinity binding, low concentrations of Mn are sufficient to induce α-synuclein fibril formation ^[13][95]. Several independent laboratories have reported the effects of Mn on the aggregation of α-synuclein ^[14][96]. The interaction between α-synuclein and Mn has been demonstrated in rat primary midbrain dopaminergic neurons, resulting in a higher intracellular level of Mn in cells with α-synuclein overexpression ^[15][16][97,98]. Although such binding of α-synuclein is protective against Mn neurotoxicity during the early stages of Mn exposure, the accumulation of sequestered Mn by α-synuclein eventually induces protein aggregation and neurotoxicity ^[17][99]. In a more recent study, these investigators demonstrated that when combined with α-synuclein, Mn exposure increases α-synuclein transmission intercellularly via exosome release ^[11][74]. By spreading the misfolded toxic α-synuclein, these exosomes induce neuroinflammation and degeneration of the nigral dopaminergic neurons ^[11][74]. This is the first in vivo demonstration that, although Mn by itself does not cause neurodegeneration, when combined with a PD-linked protein, nigral dopaminergic cell loss occurs. The results of these studies are consistent with a previous report demonstrating that α-synuclein overexpressing neuronal cells released exosomes capable of transferring α-syn protein to other normal neuronal cells ^[18][100], forming aggregates and inducing death in the receiving cell ^[19][20][101,102]. In fact, exosome-associated α-synuclein oligomers are more likely to be taken up by recipient cells and are more neurotoxic compared to free α-syn oligomers ^[21][103]. To enhance the relevance of their mouse study, Kanthasamy and colleagues isolated exosomes in the serum of welders exposed to Mn and they found increased misfolded α-synuclein in these workers as compared to the non-exposed control subjects ^[11][74]. In non-human primates, Mn exposure has also been reported to induce α-synuclein aggregation ^[22][104]. In combination, emerging evidence indicates that Mn promotes α-synuclein aggregation and spread, leading to dopaminergic neurodegeneration in experimental models and suggests that such a scenario may also occur in humans ^[23][27].

Mutations in Parkin cause autosomal recessive early-onset PD ^[24][25][105,106], which may present with or without Lewy bodies ^[25][26][106,107]. Parkin mutations are considered as the most prevalent autosomal recessive mutations in PD, accounting for approximately up to 77% of familial early-onset PD and 10–20% of early-onset PD in general ^[27][28][29][108,109,110]. Parkin is an E3 ubiquitin ligase that mediates protein degradation. Parkin has been reported to regulate Mn transport via the divalent metal transporter 1 (DMT1) ^[30][111]. DMT1 is the primary route by which Mn is taken up in the brain. Four DMT1 isoforms have been identified and the 1B isoform is regulated post-translationally and degraded via the proteasomal pathway. Parkin is involved in the ubiquitination and mediate the subsequent proteasomal degradation of this specific isoform of DMT1 ^[30][111]. Therefore, a loss of parkin function could facilitate Mn uptake, promoting Mn accumulation in the basal ganglia and accelerating its toxicity.

Mutations in DJ-1 cause early-onset autosomal recessive PD ^[31][112]. DJ-1 is a multifunctional protein. Under basal conditions, DJ-1 is localized mostly in the cytoplasm and to a lesser extent, in the mitochondria and nucleus ^[32][33][34][113,114,115]. However, under oxidative stress conditions, cytoplasmic DJ-1 translocates to mitochondria ^[34][115], where it confers protection against oxidative stress ^[34][35][115,116]. Mn has been reported to reduce the levels of DJ-1, resulting in effects that resemble the neurotoxic activity of mutant forms of DJ-1 ^[36][117]. Given that both Mn and loss of DJ-1 function can individually promote oxidative stress and induce mitochondrial dysfunction, such combination may exacerbate their neurotoxic effects. Indeed, the life-span of C. elegans was reduced after Mn exposure when DJ-1 was deleted ^[37][118].

In addition to causing autosomal recessive juvenile-onset Kufor–Rakeb syndrome ^[38][119], which is a levodopa-responsive form of pallido-pyramidal neurodegeration, homozygous missense mutations in ATP13A2 cause juvenile parkinsonism and early-onset autosomal recessive PD ^[39][120]. ATP13A2 encodes ATPase type 13A, a lysosomal P5B-type transmembrane ATPase which has functional domains like other P-type ATPases that are mainly involved in transporting cations, including Mn. Consistent with these roles of ATP13A2 and its cellular localization, loss of function in this protein has been reported to impair autophagy flux and accumulation of aggregated α-synuclein ^[40][41][42][121,122,123]. ATP13A2 has been shown to protect cells against Mn toxicity by transporting Mn into lysosomes; however, this protection is lost when mutations in this gene occur ^[42][123]. A recent study has shown that ATP13A2 polymorphism could negatively impact the effects of Mn on motor coordination in humans exposed to Mn ^[43][124].