Identification of dopaminergic neurons of the substantia nigra pars compacta as a target of manganese accumulation

Abstract

Manganese serves as a cofactor to a variety of proteins necessary for proper bodily development and function. However, an overabundance of Mn in the brain can result in manganism, a neurological condition resembling Parkinson’s disease (PD). Bulk sample measurement techniques have identified the globus pallidus and thalamus as targets of Mn accumulation in the brain, however smaller structures/cells cannot be measured. Here, X-ray fluorescence microscopy determined the metal content and distribution in the substantia nigra (SN) of the rodent brain. In vivo retrograde labeling of dopaminergic cells (via FluoroGold™) of the SN pars compacta (SNc) subsequently allowed for XRF imaging of dopaminergic cells in situ at subcellular resolution. Chronic Mn exposure resulted in a significant Mn increase in both the SN pars reticulata (>163%) and the SNc (>170%) as compared to control; no other metal concentrations were significantly changed. Subcellular imaging of dopaminergic cells demonstrated that Mn is located adjacent to the nucleus. Measured intracellular manganese concentrations range between 40–200 μM; concentrations as low as 100 μM have been observed to cause cell death in cell cultures. Direct observation of Mn accumulation in the SNc could establish a biological basis for movement disorders associated with manganism, specifically Mn caused insult to the SNc. Accumulation of Mn in dopaminergic cells of the SNc may help clarify the relationship between Mn and the loss of motor skills associated with manganism.

Manganese metabolism in humans

“…Gavin et al (1999) further indicated that a slow efflux of Mn by mitochondria accounts for the excess accumulation of Mn ions in this subcellular organelle (177). Other studies did not observe Mn accumulation in the mitochondria (152,154).…”

Brain manganese and the balance between essential roles and neurotoxicity

“…Accumulation of Mn in the brain could potentially alter multiple neurotransmitter systems and their 4 activity in the brain. Mn predominantly accumulates in the basal ganglia region of the brain including the substantia nigra, striatum and pallidum when in excess (82)(83)(84)(85). The basal ganglia have an intricate network of neurotransmitters that could potentially be altered and cause deviations in optimal physiology and behavior.…”

“…Developmental exposure of Mn caused cognitive deficits that implicate DA and brain derived neurotrophic factor (BDNF) (109). Mn accumulation in the DAergic cells of the substantia nigra pars compacta in rodent model points to a biological basis for deficits in motor skills seen in association with manganism (84). Reported effects of Mn neurotoxicity on DA include decreased DA levels (110)(111)(112), increased DA levels (113), or no modification (114) in the substantia nigra or striatum.…”

Metals and Neurodegeneration

“…Manganism is characterized by tremors, lethargy, and speech impediments, with the occasional accompaniment of psychosis 60 , 62 . Mn is elevated in dopaminergic (DAergic) neurons of the substantia nigra, providing a possible basis for the motor deficits observed in manganism 63 . Elevated Mn has been shown to affect a variety of cellular processes, including increased levels of transcription for ER-related genes 64 , ROS production 65 , mitochondrial dysfunction 66 , autophagy 67 , altered acetylcholinesterase (AChE) activity 68 , changes in cyclic AMP (cAMP) signaling 69 , iron dyshomeostatis 70 , and dysfunctional astrocytic activity 61 .…”