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. 2015 Jul 27;146(2):204–212. doi: 10.1093/toxsci/kfv099

Manganese-Induced Parkinsonism Is Not Idiopathic Parkinson’s Disease: Environmental and Genetic Evidence

Tomás R Guilarte 1,1, Kalynda K Gonzales 1
PMCID: PMC4607750  PMID: 26220508

Abstract

Movement abnormalities caused by chronic manganese (Mn) intoxication clinically resemble but are not identical to those in idiopathic Parkinson’s disease. In fact, the most successful parkinsonian drug treatment, the dopamine precursor levodopa, is ineffective in alleviating Mn-induced motor symptoms, implying that parkinsonism in Mn-exposed individuals may not be linked to midbrain dopaminergic neuron cell loss. Over the last decade, supporting evidence from human and nonhuman primates has emerged that Mn-induced parkinsonism partially results from damage to basal ganglia nuclei of the striatal “direct pathway” (ie, the caudate/putamen, internal globus pallidus, and substantia nigra pars reticulata) and a marked inhibition of striatal dopamine release in the absence of nigrostriatal dopamine terminal degeneration. Recent neuroimaging studies have revealed similar findings in a particular group of young drug users intravenously injecting the Mn-containing psychostimulant ephedron and in individuals with inherited mutations of the Mn transporter gene SLC30A10. This review will provide a detailed discussion about the aforementioned studies, followed by a comparison with their rodent analogs and idiopathic parkinsonism. Together, these findings in combination with a limited knowledge about the underlying neuropathology of Mn-induced parkinsonism strongly support the need for a more complete understanding of the neurotoxic effects of Mn on basal ganglia function to uncover the appropriate cellular and molecular therapeutic targets for this disorder.

Keywords: Parkinson’s disease, dystonia, manganese, ephedron, SLC30A10 mutation, dopamine

Idiopathic Parkinson’s disease (iPD) is a neurodegenerative disorder of the basal ganglia (see Fig. 1), characterized by a progressive loss of dopaminergic nigrostriatal connectivity between the substantia nigra pars compacta (SNpc) and dorsal striatum (ie, the caudate nucleus and putamen) (Surmeier and Sulzer, 2013). Although the complete etiology of iPD is unknown, a combination of environmental (Caudle et al., 2012; Goldman, 2014) and genetic (Lee and Liu, 2008; Vila and Przedborski, 2004) factors are thought to contribute to the expression of the parkinsonian phenotype. A significant interest has developed over the decades in the role that the natural and essential trace element manganese (Mn) plays in the manifestation of iPD. Multiple lines of evidence have revealed that long-term exposure to high levels of Mn in the occupational setting reliably leads to early cognitive alterations, depression, and hallucinations followed by movement disturbances consisting of masked facial expressions, rigidity, flexed posture, and gait impairment, as observed in iPD (Guilarte, 2010, 2013; Jankovic, 2008). However, Mn-induced parkinsonism is typically nonresponsive to the common parkinsonian therapeutic drug levodopa, a precursor for dopamine synthesis, and clinically presents with a lack of resting tremor but consistent presence of dystonia (Guilarte, 2010; Perl and Olanow, 2007). Furthermore, an absence of severe cell loss in the SNpc of individuals chronically exposed to Mn has been shown in a postmortem (nonstereological) cell-counting analysis of the midbrain (Perl and Olanow, 2007; Yamada et al., 1986). Instead, neuron degeneration and altered neurotransmitter release have been shown to occur in brain regions with abnormally high accumulation of Mn, such as the dorsal striatum, internal globus pallidus (GPi), and substantia nigra pars reticulata (SNr) (Crossgrove and Zheng, 2004; Guilarte, 2010, 2013; Perl and Olanow, 2007; Uchino et al., 2007). It is notable that these basal ganglia nuclei are anatomically and functionally interconnected through the striatal “direct pathway” (see Fig. 1) that harbors an important role in movement regulation under physiological and pathological conditions (DeLong and Wichmann 2009). Altogether, these findings suggest that degeneration of dopaminergic neurons in the SNpc may not underlie the movement anomalies of Mn-induced parkinsonism. This review will discuss the recent behavioral, pharmacological, and neuroimaging studies that comprise this viewpoint (Table 1), followed by the proposal of an alternative perspective that supports a role for nigrostriatal dopaminergic dysfunction instead of degeneration after Mn intoxication.

FIG. 1.

FIG. 1.

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Schematic showing the main connections of the basal ganglia with a special emphasis on the SNpc and VTA midbrain nuclei. The major basal ganglia pathways consist of (1) the corticostriatal and thalamostriatal glutamatergic projections to the striatum, (2) the “direct” pathway: GABAergic afferents from the striatum that directly innervate the basal ganglia output nuclei, (3) the “indirect” pathway: striatal GABAergic afferents that indirectly innervate the output nuclei via the GPe and STN, (4) the GABAergic innervation of the thalamus by the GPi and SNr, and (5) the dopaminergic and GABAergic projections from the SNpc and VTA to the dorsal and ventral striatum, respectively. Note that for simplicity some connections are not depicted in this figure, and many of the illustrated nuclei share reciprocal connections. Line thickness indicates degree of connectivity between two brain structures. Abbreviations: GABA, γ-Aminobutyric acid; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; SNpc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus; VP, ventral pallidum. See DeLong and Wichmann (2009), Haber and Knutson (2010), and Yetnikoff et al. (2014) for more details.

TABLE 1.

Comparison of Dopaminergic Changes Between Subjects With Idiopathic PD, Dystonia, Mn-Induced Parkinsonism, Ephedron-Induced Parkinsonism, or SLC30A10 Mutation Parkinsonism

Category Idiopathic PD Dystonia Mn-induced parkinsonism Ephedron-induced parkinsonism SLC30A10 mutation parkinsonism
Responsiveness to levodopa Yes Nonresponsive in majority of cases, except for dopa-responsive dystonia (DRD) Nonresponsive Nonresponsive Nonresponsive
TH+ cell loss in the SNpc Yes—substantial and progressive Enzymatic defects in dopamine synthesis without cell loss No—qualitative observations in occupational exposures — Depigmentation without cell loss—qualitative observations
TH+, DAT+, or VMAT2+ immunoreactivity in the dorsal striatum Reduced—substantial for TH, DAT, and VMAT2; only preserved in the medial dorsal striatum Normal in most forms of dystonia Normal in Mn-exposed monkeys — —
Dopamine release in the dorsal striatum Markedly reduced Reduced in some forms of dystonia Markedly reduced in Mn-exposed monkeys (> 50%) — —
Fluorodopa uptake in dorsal striatum(neuroimaging) Markedly reduced Normal in DRD but reduced in adult-onset dystonia Normal in striatum of smelters; slightly reduced in caudate of welders; normal in Mn-exposed monkeys — —
DAT levels in dorsal striatum (neuroimaging) Markedly reduced Normal in DRD and most forms of dystonia Slightly reduced in smelters; normal in Mn-exposed monkeys Normal Normal
D2 dopamine receptor levels in dorsal striatum(neuroimaging) No change or increased Increased in DRD but normal or reduced in other forms of dystonia Decreased in caudate of smelters; slightly reduced in Mn-exposed monkeys — —
VMAT2 levels in dorsal striatum (neuroimaging) Markedly reduced Increased in DRD Normal in smelters — —
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CHRONIC EXPOSURE TO MN: NIGROSTRIATAL DOPAMINE TERMINAL DYSFUNCTION IN THE ABSENCE OF DEGENERATION

The use of neuroimaging modalities, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), have been valuable in visualizing and measuring the degree of dopaminergic neuron degeneration in the striatum of iPD patients (see Table 1) and parkinsonian animal models (Pavese and Brooks, 2009; Stoessl, 2012). In parallel with progressive nigral cell loss and movement impairments, PET and SPECT imaging of dopaminergic presynaptic terminals has shown significantly diminished uptake of [18F]-fluorodopa (representative of levodopa metabolism in axon terminals) and dopamine transporters (DATs), along with either no change or increased [11C]-raclopride binding to D2-dopamine receptors (D2Rs), throughout the dorsal striatum of individuals with advanced iPD, whereas the dorsal posterior putamen is primarily affected in early iPD (Blesa et al., 2012; Chen et al., 2008; Criswell et al., 2011; Guilarte, 2010; Huang, 2007; Huang et al., 2007; Pavese and Brooks, 2009; Stoessl, 2012). PET studies using vesicular monoamine transporter-type 2 (VMAT-2) ligands demonstrated further deficiencies in the presynaptic integrity of nigrostriatal dopaminergic afferents in iPD (Blesa et al., 2012; Stoessl, 2012). In regard to occupational Mn exposures (Table 1), normal [18F]-fluorodopa- and VMAT-2-PET in the striatum but decreased [11C]-raclopride uptake in the caudate were reported in levodopa-resistant Taiwanese smelter workers who were clinically presented with psychiatric symptoms, dystonia, gait abnormalities, bradykinesia, rigidity, masked face, and micrographia (Huang, 2007; Huang et al., 2015). Furthermore, normal or slightly reduced [99MTc]-TRODAT-1 SPECT to measure DAT was detected in the same Mn-exposed smelters relative to healthy controls (Huang, 2007). However, after chronic exposure to Mn in welding fumes, welders who were asymptomatic but slightly impaired in their clinical motor examination displayed a significant reduction (approximately 11%) in [18F]-fluorodopa uptake in the caudate nucleus with no effect on the putamen (Criswell et al., 2011). Overall, the [18F]-fluorodopa uptake patterns and DAT and VMAT-2 levels in the dorsal striatum differ between individuals exposed to Mn and those afflicted with iPD (Table 1). It should be noted that direct comparisons between iPD and Mn-induced parkinsonism are problematic, because former analyses were performed in the absence or presence of levodopa replacement therapy in iPD patients and at diverse time points in the disease progression. In addition, individuals with Mn intoxication may have undiagnosed iPD, further complicating the interpretation of neuroimaging and therapeutic outcomes.

Nonhuman primates acutely or chronically exposed to moderate levels of Mn under highly controlled conditions displayed levodopa-resistant motor disturbances, deficits in overall activity levels and fine motor skills, and abnormally high levels of Mn in the basal ganglia nuclei (see Fig. 2; Guilarte et al., 2006; Perl and Olanow, 2007; Schneider et al., 2006). Normal [18F]-fluorodopa PET and postmortem dopamine levels, but with co-existing decreased [11C]-raclopride (reflective of D2R) uptake, occurred in the dorsal striatum after acute Mn exposure (Perl and Olanow, 2007). In another study, PET neuroimaging of chronic Mn-exposed animals revealed a marked (>50%) reduction in amphetamine-induced dopamine release, normal [11C]-methylphenidate (DAT) uptake, and a small reduction in [11C]-raclopride uptake in the dorsal striatum, although dopamine levels were unchanged in this region (Guilarte, 2010; Guilarte et al., 2006, 2008). These data provide the first evidence that movement disturbances associated with Mn intoxication may result from the marked inhibition of striatal dopamine release in the absence of nigrostriatal dopaminergic terminal degeneration (Guilarte, 2010; Guilarte et al., 2006, 2008). Although nonhuman primates exposed to acute or chronic Mn express some parkinsonian movement abnormalities, these collective findings demonstrate an intact but dysfunctional nigrostriatal dopaminergic system in these animals, as occurs in occupationally exposed individuals (Table 1). The predictability of the nonhuman primate model may thus provide an efficient means to delineate the pathogenesis of Mn-related movement disturbances.

FIG. 2.

FIG. 2.

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T1-weighted MRI images of the same monkey brain at the level of the globus pallidus before (A) and after (B) 17 months of Mn administration (cumulative dose of 3335.2 mg Mn). Mn administration produces bilateral hyperintensive signal throughout the brain relative to baseline images. Abbreviation: C/P, caudate/putamen; GP, globus pallidus; LHb, lateral habenula.

Densities of dopaminergic afferents immunolabeled for DAT, tyrosine hydroxylase (TH, the dopamine synthesizing enzyme), or VMAT-2, were preserved only in the medial caudate-putamen of advanced iPD brains (Miller et al., 1999; Porrit et al., 2005; Wilson et al., 1996). However, postmortem receptor autoradiography showed a reduction in DAT and VMAT-2 levels in all striatal regions of these brains, which resembled the progressive, regional pattern of loss in iPD neuroimaging studies (Miller et al., 1999; Porrit et al., 2005; Wilson et al., 1996). In contrast, dopamine and other markers of dopaminergic terminal integrity, such as TH, DAT, and VMAT-2 were unaltered by Mn toxicity in the dorsal striatum of nonhuman primates exposed to Mn, when compared with their appropriate controls (Guilarte et al., 2008; Perl and Olanow, 2007). Similar types of analyses remain to be performed in the postmortem brain tissue of Mn-intoxicated humans.

In accordance with the nonhuman primate findings, subsequent rodent studies that utilized fast-scan cyclic voltammetry and microdialysis with HPLC-electrochemical detection have shown that acute or chronic Mn exposure attenuated dopamine release with no effect on dopamine concentrations in the striatum (Baek et al., 2007; Khalid et al., 2011; Peneder et al., 2011). In addition, nonstereological cell quantification demonstrated that the number of dopamine neurons in the SNpc was unchanged by Mn intoxication in these rodent studies (Baek et al., 2007; Peneder et al., 2011). It is noteworthy to mention that other groups have shown reduced striatal dopamine and dopamine metabolite levels after intrastriatal Mn injections in rats (Brouillet et al., 1993), and the loss of dopaminergic neurons in the SNpc, dopamine depletion in the striatum and movement abnormalities that are responsive to levodopa therapy in animals chronically exposed to Mn via inhalation (Sanchez-Betancourt et al., 2012). Therefore, a more detailed understanding of the toxicological effects of Mn on the function of midbrain dopaminergic systems and their targets will assist in the interpretation of these conflicting findings.

SUPPORTING EVIDENCE FROM RECENT ATYPICAL HUMAN CASES OF MN INTOXICATION

Clinical studies have revealed abnormally high-brain Mn concentrations accompanied with parkinsonism in two different groups of human subjects: (1) young drug users intravenously injecting the Mn-containing psychostimulant drug ephedron and (2) individuals with inherited autosomal recessive mutations of the SLC30A10 gene recognized as an Mn transporter. Collective findings from these clinical subpopulations complement previous studies that indicate Mn-induced parkinsonism may involve nigrostriatal terminal dysfunction in an intact dopaminergic system (see Table 1).

Parkinsonism in Intravenous Ephedron Users

Over the last decade, numerous clinical reports from eastern and western European countries, Russia, and Canada have shown that young individuals who abuse ephedron (also called methcathinone) rapidly present (approximately 6 months after use) with emotional, cognitive, and movement abnormalities similar to those in Mn-induced parkinsonism, which continue to persist even after drug abstinence (Colosimo and Guidi, 2009; de Bie et al., 2007; Fudalej et al., 2013; Iqbal et al., 2012; Janocha-Litwin et al., 2014; Meral et al., 2007; Poniatowska et al., 2014; Sanotsky et al., 2007; Selikhova et al., 2008; Sikk et al., 2010, 2013; Stepens et al., 2008; Yildirim et al., 2009). These recreational ephedron users are reminiscent of parkinsonian cases discovered in the early 1980s, where irreversible parkinsonism was induced by the intravenous injection of an illicit opiate analog (meperidine) that was incorrectly synthesized into the nigrostriatal dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Davis et al., 1979; Langston et al., 1983). As a result, MPTP-induced parkinsonism resides as one of the most common parkinsonian animal models used in research today based on its ability to replicate many aspects of the neuropathological and clinical symptoms of iPD (Bezard and Przedborski, 2011). Thus, it can be proposed that a similar correlation may exist between parkinsonism induced by ephedron and occupational and environmental Mn intoxication, supplying a potential means to further delineate the underlying mechanisms of Mn-induced parkinsonism.

Ephedron displays similar biochemical and addictive properties as the highly abused psychostimulants amphetamine and methamphetamine and is easily synthesized from over the counter pharmaceuticals ephedrine and pseudoephedrine (Emerson and Cisek, 1993). However, unlike methamphetamine synthesis, potassium permanganate is used for the homemade production of ephedron, thereby creating high levels of Mn byproduct (Sikk et al., 2007). Ephedron users consequentially have increased blood Mn levels due to their intravenous injection of this homemade mixture (Fudalej et al., 2013; Janocha-Litwin et al., 2014; Poniatowska et al., 2014; Selikhova et al., 2008; Sikk et al., 2010, 2013; Stepens et al., 2008). As observed with occupational exposures to Mn toxicity, these individuals are levodopa-resistant (Colosimo and Guidi, 2009; Fudalej et al., 2013; Janocha-Litwin et al., 2014; Poniatowska et al., 2014; Sanotsky et al., 2007; Selikhova et al., 2008; Sikk et al., 2013; Stepens et al., 2008) and displayed abnormally high Mn concentrations in T1-weighted MRI images of the globus pallidus, striatum, and midbrain (Fudalej et al., 2013; Janocha-Litwin et al., 2014; Poniatowska et al., 2014; Selikhova et al., 2008; Sikk et al., 2010, 2013; Stepens et al., 2008). Furthermore, SPECT neuroimaging studies revealed normal striatal DAT uptake in ephedron users despite their expression of moderate to severe parkinsonism (Colosimo and Guidi, 2009; Sanotsky et al., 2007; Selikhova et al., 2008), in contrast to that observed after methamphetamine use (Volkow et al., 2001) and in iPD (Blesa et al., 2012; Chen et al., 2008; Criswell et al., 2011; Huang, 2007; Huang et al., 2007; Pavese and Brooks, 2009; Stoessl, 2012). In support of Mn being the etiological agent, ephedron-induced parkinsonism has not been reported to our knowledge in the United States, where ephedron is synthesized without potassium permanganate and the subsequent Mn byproduct (Emerson and Cisek, 1993; Stepens et al., 2008). Findings from these collective studies further support our view that the motor symptoms affiliated with ephedron (Mn)-induced parkinsonism may not transpire from the degeneration of nigrostriatal dopaminergic afferents or the depletion of striatal dopamine as is the case in iPD (see Table 1). However, although much has been learned from these neuroimaging studies, detailed postmortem analyses are essential to fully determine the underlying neuropathology in persons who abuse ephedron.

Parkinsonism in Inherited Autosomal Recessive Mutations of the SLC30A10 Gene

Parkinsonism including that induced by Mn neurotoxicity encompasses a spectrum of onset times (early vs late), degrees of severity, and individual symptoms (Hoehn and Yahr, 1967; Jankovic, 2008; Lees, 2007). Thus, the etiology of Mn-induced parkinsonism is thought to involve a combination of genetic and environmental factors (Hardy et al., 2009; Klein and Schlossmacher, 2007), such that the genetic susceptibility to environmental Mn intoxication or the genetic initiation of neurotoxic insults by endogenous Mn may contribute to these clinical inconsistencies in Mn-induced parkinsonism.

Supporting evidence originates from recent, successive clinical reports of genetically derived Mn neurotoxicity induced by mutations in the SLC30A10 gene of centrally located neurons (ie, the basal ganglia nuclei) and liver cells (Table 1) (Gospe et al., 2000; Quadri et al., 2012; Tuschl et al., 2012). Qualitative examinations of the globus pallidus and liver from these affected individuals revealed a reduction in SLC30A10 immunostaining in comparison with control human tissue (Lechpammer, 2014; Quadri et al., 2012). A recent study using cultured cells, primary midbrain neurons, and Caenorhabditis elegans has shown that the SLC30A10 plasma membrane protein maintained physiological intracellular Mn concentrations by regulating Mn efflux activity through its transporter function (Leyva-Illades et al., 2014). On the other hand, the abnormal SLC30A10 proteins resulting from inherited autosomal recessive SLC30A10 mutations were confined to the endoplasmic reticulum, indicating a likely compromise in their ability to export Mn from the cell. In the same neurons, the SLC30A10 mutations did not impair cell viability but heightened their sensitivity to Mn toxicity. The resultant factor could be toxic intracellular accumulation of Mn that interferes with cellular function in the brain and liver.

Affected individuals initially displayed dystonia in childhood or parkinsonian-like motor symptoms as adults, and over time, these motor complications progressively worsened in all situations (Gospe et al., 2000; Quadri et al., 2012; Tuschl et al., 2012). Prior to their knowledge, Gospe et al. (2000) described the first case of this disorder in a 14-year-old male who presented with progressive spastic paraparesis of the lower limbs with subsequent gait stiffness, hepatic myelopathy, polycythemia, depleted iron stores (ie, low ferritin and high total iron-binding capacity), and highly elevated blood, liver, and basal ganglia Mn levels (ie, hypermanganesemia). Two decades later, this individual displayed movement abnormalities associated with spastic paraparesis and increased Mn levels in the liver and basal ganglia nuclei, but lacked the development of true parkinsonism and extrapyramidal symptoms (Gospe et al., 2000; Lechpammer et al., 2014; Tuschl et al., 2012). Subsequent reports of inherited Mn intoxication described a similar clinical picture, except for the occurrence of extrapyramidal symptoms such as dystonia with a subsequent “cock-walk” gait instead of spastic paraparesis, in 2 siblings from a consanguineous family (Brna et al., 2011; Tuschl et al., 2008), along with 13 individuals from 7 isolated families (Brna et al., 2011; Gospe et al., 2000; Sahni et al., 2007; Tuschl et al., 2012). Complete genome mapping of these subjects revealed homozygous sequence changes in the SLC30A10 gene that triggered decreases in the protein expression and Mn exporter/transporter function of SLC30A10, providing the first genetic evidence that links Mn neurotoxicity with an inherited autosomal recessive disorder (Lechpammer et al., 2014; Quadri et al., 2012; Tuschl et al., 2012).

The comparison of Mn neurotoxicity induced by environmental factors versus SLC30A10 mutations exposes both similarities and differences in their detrimental effects and treatment responses (Table 1), although comparative data do not exist for all individuals. In resemblance, neuropathological analyses in the first subject described by Gospe et al. (2000) showed possible signs of neuronal loss in the globus pallidus and dorsal striatum, whereas depigmentation without cell loss (nonstereological analyses) occurred in the midbrain (Lechpammer et al., 2014). SPECT imaging in 3 subjects with SLC30A10 mutations revealed normal striatal DAT levels as observed in occupational exposures to Mn toxicity (Quadri et al., 2012; Stamelou et al., 2012). Those mutation carriers who received levodopa/carbidopa administration were resistant to its beneficial effects on parkinsonism (Quadri et al., 2012), with the exception of one case in which mild improvement was noted at the beginning of the treatment but was not sustained (Stamelou et al., 2012). In regard to differences between the two types of Mn intoxication, the blood Mn levels of SLC30A10 mutation carriers were considerably higher than those described in environmentally exposed individuals (Burkhard et al., 2003; Quadri et al., 2012; Sikk et al., 2010, 2013; Stamelou et al., 2012; Tuschl et al., 2012), and polycythemia and reduced iron levels have only been described in Mn neurotoxicity associated with SLC30A10 mutations (Stamelou et al., 2012) or in cell lines exposed to toxic levels of Mn (DeWitt et al., 2013). Together, these findings support the likelihood that factors other than dopaminergic neuron degeneration in the SNpc are responsible for the motor symptoms induced by SLC30A10 mutations and toxic environmental conditions.

Chelation therapy with disodium calcium EDTA partially alleviated motor symptoms and significantly reduced elevated blood Mn levels in SLC30A10 mutation subjects (DiToro Mammarella et al., 2014; Quadri et al., 2012; Stamelou et al., 2012; Tuschl et al., 2008). These observed beneficial effects of chelation therapy may be associated with cellular or molecular processes that are inhibited only in the presence of Mn, rather than by frank neurodegeneration. From this perspective, Mn inhibition of striatal dopamine release, which has been documented in Mn exposed nonhuman primates (Guilarte et al., 2006, 2008) and rodents (Khalid et al., 2011), may be reversible if brain Mn levels are reduced. PET studies of in vivo dopamine release in human subjects with the SLC30A10 mutation, as well as in other human conditions of Mn intoxication, can assist in defining the relationship between chelation therapy-induced reversibility of movement abnormalities and Mn-induced inhibition of striatal dopamine release. On the other hand, iron supplementation had additive beneficial effects to the chelation treatment in these mutation carriers (DiToro Mammarella et al., 2014; Quadri et al., 2012; Stamelou et al., 2012; Tuschl et al., 2008), leading to the proposal of early treatment with both chelators and iron to prevent symptom progression (Lechpammer et al., 2014; Tuschl et al., 2008). However, the augmented signal intensity in the basal ganglia nuclei of SLC30A10 mutation carriers remained the same after these treatments (DiToro Mammarella et al., 2014; Stamelou et al., 2012; Tuschl et al., 2008), implying that Mn has long-lasting negative effects on the central nervous system that are resistant to the current therapeutic agents for Mn-induced parkinsonism.

CONCLUDING REMARKS

A significant amount of evidence clearly indicates that Mn intoxication either of environmental (occupational or drug-induced) or genetic (SLC30A10 mutation) origin results in atypical parkinsonism associated mainly with dystonia, rigidity, fine motor control deficits, a “cock-walk” gait (ie, high stepping), and speech disturbances. In contrast to iPD (Surmeier and Sulzer, 2013) but similar to many forms of dystonia (Neychev et al., 2011; Wichmann, 2008), the development of this spectrum of motor symptoms likely originates from intact, but dysfunctional midbrain dopaminergic systems. Because of their large dopaminergic innervation and susceptibility to Mn toxicity, other basal ganglia nuclei, such as the dorsal striatum, GPi, and SNr (ie, the striatal “direct pathway”; Fig. 1), and intrastriatal GABAergic and cholinergic circuits, may have fundamental roles in the development and/or maintenance of Mn-induced parkinsonism (Burton et al., 2009; DeLong and Wichmann, 2009; Finkelstein et al., 2007; Guilarte, 2013) similar to iPD (Bonsi et al., 2011; DeLong and Wichmann, 2009) and dystonia (Neychev et al., 2011; Starr et al., 2005; Wichmann, 2008). Interestingly, a recent study of in vivo extracellular recordings in rats revealed alterations in firing rates and patterns of “indirect pathway” neurons (ie, the lateral globus pallidus and subthalamic nucleus [STN]; Fig. 1) after the administration of daily, low doses of Mn (Bouabid et al., 2014). If both the “direct” and “indirect” pathways are modified by Mn intoxication, the abnormal striatal outflow to the basal ganglia output nuclei would transform the downstream activity of thalamic and cortical areas functionally related to these structures (Fig. 1), which is clearly observed in parkinsonism (DeLong and Wichmann, 2009) and dystonia (Neychev et al., 2011; Starr et al., 2005). Thus, the underlying physiological mechanisms of movement disturbances associated with Mn-induced parkinsonism may share similarities with dystonia but not iPD in spite of incorporating similar neural circuits. Future biochemical and electrophysiological analyses in clinical populations and animal models will allow for a clearer understanding of the etiology and pathogenesis of these circuit disorders.

Dopamine neurons are regulated by a heterogeneous group of neurochemicals expressed either endogenously (calbindin and neuromelanin) or by their afferents from the striatum, globus and ventral pallidum (VP), extended amygdala, bed nucleus of stria terminalis, pedunculopontine nucleus, dorsal raphe, lateral habenula (LHb), and superior colliculus (Haber and Knutson, 2010; Hikosaka et al., 2008; Smith and Villalba, 2008; Zecca et al., 2003). Collectively, these systems form intricate feedforward and feedback loops that mediate various behavioral outcomes, such as reward processing and motor control (Haber and Knutson, 2010). Because impaired movement, working memory, and striatal dopamine release occur in Mn-induced parkinsonism (Guilarte, 2013), chronic Mn intoxication likely disturbs these dopamine-regulating systems leading to dysfunctional dopaminergic activity across their complex neural networks (see Fig. 1). For example, regional patterns of dysfunction (but not degeneration) of mesencephalic dopamine neurons may occur in response to Mn neurotoxicity as in iPD, where the dopamine-positive/neuromelanin-positive/calbindin-negative ventral tier of the SNpc is the first and most severely affected midbrain region (Damier et al., 1999; Poewe and Wenning, 1998). In addition, extrastriatal dopaminergic regions such as the prefrontal cortex may be negatively affected by Mn intoxication (Guilarte, 2013) as in iPD (Smith and Villalba, 2008). Nigral neurons that contain either neuromelanin or calbindin (Fig. 1) have been shown to be resistant or susceptible to particular neurotoxic insults and disease processes, including dystonia and parkinsonism (Smith and Villalba, 2008; Zecca et al., 2003). Thus, neuromelanin-containing dopaminergic neurons have demonstrated a resistance to Mn toxicity in occupationally exposed humans (Perl and Olanow, 2007), whereas depigmentation occurred in intact dopaminergic neurons in the brains of individuals with SLC30A10 mutations (Lechpammer, 2014). Even though normal striatal levels for various dopaminergic markers were found after chronic Mn exposure (Guilarte, 2010, 2013), the possibility exists for altered DAT, VMAT-2, and dopamine receptor expression and function within the midbrain itself (Harrington et al., 1996; Nirenberg et al., 1996). In addition, the γ-aminobutyric acid (GABA)-containing neurons in the VTA and SNpc (Fig. 1) that on occasion coexpress dopamine (Korotkova et al., 2004; Nair-Roberts et al., 2008; Yetnikoff et al., 2014) may be negatively affected by chronic Mn exposure. Through the use of the nonhuman primate model of Mn-induced neurotoxicity, similar pathological studies as performed in dystonic and parkinsonian patients and animal models could reveal the dopamine-regulating systems and functional subregions of the midbrain that are susceptible to Mn-induced injury.

FUTURE DIRECTIONS

Clinical and experimental discoveries suggest that the progressive motor and nonmotor symptoms of Mn-induced parkinsonism may result from impaired dopamine release in the striatum along with compromised function of specific neuronal population(s) intrinsic to the basal ganglia. However, defining the neuroanatomical substrates affected by Mn in various basal ganglia nuclei, as well as the absolute number of dopaminergic neurons in the midbrain, is critically important for our advanced understanding of the cellular and neurochemical bases of the movement abnormalities, such as dystonia, associated with excess levels of Mn in the brain, and possibly, some forms of atypical parkinsonism. In addition, in vivo neuroimaging of individuals expressing the SLC30A10 mutation or ephedron users will provide further clarification for these disease processes. Because no effective treatment currently exists to completely reverse the neurological consequences of Mn intoxication, future development of therapeutic interventions could be achieved through these studies to alleviate the levodopa- and chelation-resistant aspects of neurological impairments of environmental, drug, and genetic Mn-induced parkinsonism.

FUNDING

The National Institutes of Environmental Health Sciences (ES010975 to T.R.G. and P30E5009089); a Columbia University Provost Postdoctoral Research Scientist Award (to K.K.G.).

ACKNOWLEDGMENTS

The authors would like to express our thanks and gratitude to Meredith K. Loth, MPH and Jennifer L. McGlothan, MS for reading and editing the manuscript.

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