The vesicular monoamine transporter 2 (VMAT2; SLC18A2) is responsible for packaging dopamine into vesicles for subsequent release and has been suggested to serve a neuroprotective role in the dopamine system. Here, we show that mice that express ∼5% of normal VMAT2 (VMAT2 LO) display age-associated nigrostriatal dopamine dysfunction that ultimately results in neurodegeneration. Elevated cysteinyl adducts tol-DOPA and DOPAC are seen early and are followed by increased striatal protein carbonyl and 3-nitrotyrosine formation. These changes were associated with decreased striatal dopamine and decreased expression of the dopamine transporter and tyrosine hydroxylase. Furthermore, we observed an increase in α-synuclein immunoreactivity and accumulation and neurodegeneration in the substantia nigra pars compacta in aged VMAT2 LO mice. Thus, VMAT2 LO animals display nigrostriatal degeneration that begins in the terminal fields and progresses to eventual loss of the cell bodies, α-synuclein accumulation, and anl-DOPA responsive behavioral deficit, replicating many of the key aspects of Parkinson's disease. These data suggest that mishandling of dopamine via reduced VMAT2 expression is, in and of itself, sufficient to cause dopamine-mediated toxicity and neurodegeneration in the nigrostriatal dopamine system. In addition, the altered dopamine homeostasis resulting from reduced VMAT2 function may be conducive to pathogenic mechanisms induced by genetic or environmental factors thought to be involved in Parkinson's disease.

Paraquat, MPTP, and rotenone reproduce features of Parkinson's disease (PD) in experimental animals. The exact mechanisms by which these compounds damage the dopamine system are not firmly established, but selective damage to dopamine neurons and inhibition of complex I are thought to be involved. We and others have previously documented that the toxic metabolite of MPTP, MPP⁺, is transported into dopamine neurons through the dopamine transporter (DAT), while rotenone is not transported by DAT. We have also demonstrated the requirement for complex I inhibition and oxidative damage in the dopaminergic neurodegeneration produced by rotenone. Based on structural similarity to MPP⁺, it has been proposed that paraquat exerts selective dopaminergic toxicity through transport by the DAT and subsequent inhibition of mitochondrial complex I. In this study we report that paraquat is neither a substrate nor inhibitor of DAT. We also demonstrate that in vivo exposure to MPTP and rotenone, but not paraquat, inhibits binding of ³H-dihydrorotenone to complex I in brain mitochondria. Rotenone and MPP⁺ were both effective inhibitors of complex I activity in isolated brain mitochondria, while paraquat exhibited weak inhibitory effects only at millimolar concentrations. These data indicate that, despite the apparent structural similarity to MPP⁺, paraquat exerts its deleterious effects on dopamine neurons in a manner that is unique from rotenone and MPTP.

Alzheimer disease (AD) is the most common neurodegenerative disease worldwide and cases are expected to increase 3-fold over the next 40 years.¹ The most common form of AD is the late-onset form, which typically develops after 60 years of age. The etiological factors of late-onset AD are not yet completely understood but include genetic, environmental, and lifestyle factors that influence a person’s risk for developing the disease.² Although there is a growing list of AD susceptibility genes, only having an apolipoprotein E4 (APOE4) allele has a relatively strong effect (relative risk approximately 2-3), and, cumulatively, the more than 10 genes identified thus far account for only less than half of AD cases.³ To our knowledge, few studies have explored the potential of environmental exposures to contribute to AD, but occupational exposure to metals, solvents, and pesticide is reported to be a potential environmental contributor.^4,5 Previously, we reported that serum levels of p,p’-dichlorodiphenyldichloroethylene (DDE), a metabolite of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT), were significantly higher in a small cohort (n = 20) of patients with AD compared with control participants, and that there was a significant association between DDE levels and a diagnosis of AD.⁶ In the present study, we evaluated the associations between serum DDE levels, AD, and Mini-Mental State Examination (MMSE) scores in a larger number of cases and control participants from 2 geographical sites, and we explored differential susceptibility by APOE4 genotype status. We also examined the relationship between brain and serum levels of DDE and whether DDT or DDE alters the expression of the amyloid precursor protein (APP) in cultured neuronal cells.

Spinal long-term potentiation (LTP) at C-fiber synapses is hypothesized to underlie chronic pain. However, a causal link between spinal LTP and chronic pain is still lacking. Here, we report that high-frequency stimulation (HFS; 100 Hz, 10 V) of the mouse sciatic nerve reliably induces spinal LTP without causing nerve injury. LTP-inducible stimulation triggers chronic pain lasting for more than 35 days and increases the number of calcitonin gene-related peptide (CGRP) terminals in the spinal dorsal horn. The behavioral and morphological changes can be prevented by blocking NMDA receptors, ablating spinal microglia, or conditionally deleting microglial brain-derived neurotrophic factor (BDNF). HFS-induced spinal LTP, microglial activation, and upregulation of BDNF are inhibited by antibodies against colony-stimulating factor 1 (CSF-1). Together, our results show that microglial CSF1 and BDNF signaling are indispensable for spinal LTP and chronic pain. The microglia-dependent transition of synaptic potentiation to structural alterations in pain pathways may underlie pain chronicity.