Parkinson's disease (PD) is the second most common neurodegenerative disorder in the elderly, affecting 2% of the population over 60 years old . The classic form of PD is manifested clinically by resting tremor and postural instability, along with variable non-motor symptoms. Neuropathologically, PD is characterized by the loss of dopaminergic neurons mainly in the substantia nigra pars compacta accompanied by the formation of intracytoplasmic inclusions known as Lewy bodies, containing α-synuclein. Neurodegeneration in PD affects primarily the striatonigral system, but cases with cognitive impairment present more widespread degeneration including neuronal populations in the striatum, hippocampus, and neocortex [2, 3]. Therefore, PD associated pathology not only has an impact on the degeneration of mature dopaminergic neurons in the basal ganglia, but could also influence neurogenesis in the adult brain , where neural stem and progenitor cells are still present in the hippocampal dentate gyrus and the subventricular zone (SVZ), and continuously generate new neurons [5–7].
From etiology, PD is believed to be a multifactorial disease where environmental factors might act on genetically predisposed individuals . Only a small fraction of PD occurrence (about 5 % of cases) are inherited in a recessive or dominant manner and are associated with mutations in genes including SNCA, LRRK2, DJ1, PINK1
and UCHL-1[9, 10]. Although mutations in the SNCA gene (encoding for α-synuclein) are rare, the crucial roles of α-synuclein in PD pathology, including aberrant calcium homoeostasis and mitochondrial fragmentation, is supported by multiple neuropathological and biochemical evidence.
Mutations in the same genes can be involved in familial PD and also be risk factors for sporadic manifestations; suggesting that inherited and idiopathic PD share common pathological mechanisms . While accumulation/missfolding of α-synuclein might play more prominent roles in PD sporadic manifestations, mutations in the LRRK2 gene, encoding leucine-rich repeat kinase 2, are the most prevalent cause of autosomal dominantly inherited PD, which are characterized by brainstem Lewy body pathology. The most frequent mutation, LRRK2(G2019S) is located in the kinase domain of the protein increasing kinase activity  and has the highest genotype- and population-attributable risk .
We have recently shown that accumulation of α-synuclein in the limbic system might contribute to the neurodegenerative phenotype by interfering with adult neurogenesis in transgenic mice models [14, 15]. We reported reduced proliferation and neuronal maturation accompanied by increased apoptosis in murine embryonic stem (mES) cells overexpressing wild type and mutant α-synuclein, and in the hippocampal subgranular zone of α-synuclein transgenic mice. These alterations were accompanied by a reduction in Notch-1 and Hairy and Hes-5 mRNA and protein levels .
LRRK2 protein, on the other hand, shows widespread, neuronal-specific expression in the adult mammalian brain, and is highly expressed in the hippocampus and subventricular zone (SVZ) , suggesting its role in neurogenesis. LRKK2 have been recently implicated in modulation of neuronal differentiation in murine embryonic stem cells . Moreover, adult neurogenesis and neurite outgrowth have been reported to be impaired in LRKK2(G2019S) mice .
Besides genetic-linked manifestations, the majority of PD cases are of idiopathic origin, whose etiology is yet not completely understood. Recent studies however, suggest that interactions between environmental toxins and genetic polymorphisms might play a role. Neurotoxins, including agrichemicals might lead to neurodegeneration by triggering accumulation of α-synuclein in subcortical and cortical regions . Concurrent exposure to the herbicide Paraquat (PQ) and the fungicide Maneb (MB) in adult mice led to significantly dopamine (DA) fiber loss, altered DA turnover and decreased locomotor activity [21, 22]. Moreover, combined exposure to MB and PQ in rural workers was reported to increase the risk of developing PD by 75% in agricultural areas of California . PQ is one the most used herbicides worldwide. PQ exerts its toxicity by cellular redox cycling with the formation of superoxide radicals and it is believed that mitochondrial complex I is a primary target . MB, used as a fungicide, seems to cross the brain blood barrier and, although its mechanisms of toxicity are not very well known, it seems to preferentially inhibit mitochondrial complex III .
Although extensive research has been conducted on the effects of pesticides on the dopaminergic system in the PD brain, a possible impact of pesticide exposure on adult neurogenesis remained to be explored.
We extended here our previous studies on adult hippocampal neurogenesis [4, 14–16, 19] in two different transgenic mice mouse models of PD generated in our laboratory, the Line 61, expressing the human wild type SNCA gene and Line 29 that expresses LRRK2(G2019S), by investigating the effects of MB and PQ exposure and with the aim to model gene x environment interactions in familial and sporadic PD manifestations. Our findings show that α-synuclein missfoldig/accumulation, LRRK2 gene mutation G2019S and exposure to the agrichemicals Maneb and Paraquat have deleterious effects on adult neurogenesis, contributing to overall PD pathology.