Glial A30P alpha-synuclein pathology segregates neurogenesis from anxiety-related behavior in conditional transgenic mice

Abstract

In Parkinson’s disease (PD) patients, alpha-synuclein (α-syn) pathology advances in form of Lewy bodies and Lewy neurites throughout the brain. Clinically, PD is defined by motor symptoms that are predominantly attributed to the dopaminergic cell loss in the substantia nigra. However, motor deficits are frequently preceded by smell deficiency or neuropsychological symptoms, including increased anxiety and cognitive dysfunction. Accumulating evidence indicates that aggregation of α-syn impairs synaptic function and neurogenic capacity that may be associated with deficits in memory, learning and mood. Whether and how α-syn accumulation contributes to neuropathological events defining these earliest signs of PD is presently poorly understood. We used a tetracycline-suppressive (tet-off) transgenic mouse model that restricts overexpression of human A30P α-syn to neurons owing to usage of the neuron-specific CaMKIIα promoter. Abnormal accumulation of A30P correlated with a decreased survival of newly generated neurons in the hippocampus and olfactory bulb. Furthermore, when A30P α-syn expression was suppressed, we observed reduction of the human protein in neuronal soma. However, residual dox resistant A30P α-syn was detected in glial cells within the hippocampal neurogenic niche, concomitant with the failure to fully restore hippocampal neurogenesis. This finding is indicative to a potential spread of pathology from neuron to glia. In addition, mice expressing A30P α-syn show increased anxiety-related behavior that was reversed after dox treatment. This implies that glial A30P α-synucleinopathy within the dentate gyrus is part of a process leading to impaired hippocampal neuroplasticity, which is, however, not a sole critical event for circuits implicated in anxiety-related behavior.

Long-term treatment with l-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease

“…Neuropsychiatric disorders, such as depression, anxiety and cognitive impairment can respond to dopaminergic therapy (Chaudhuri and Schapira, 2009). Hippocampal adult neurogenesis was recently studied in animal models (Hinkle et al, 2012;Kohl et al, 2012;Marxreiter et al, 2013) and in PD patients (Höglinger et al, 2004), linking adult neurogenesis to depression-like behavior and cognitive dysfunction in PD. In addition, dysfunction of the catecholaminergic system in the limbic system seems to be related to the symptom of depression (Remy et al, 2005), which responds to dopaminergic therapy with L-DOPA and/or PPX (Barone et al, 2010;Rektorova et al, 2005).…”

“…In a post-mortem study of PD patients, a decreased number of neural progenitor cells in the dentate gyrus and the OB has been found, suggesting a downregulation of neurogenesis in both neurogenic regions (Höglinger et al, 2004). In transgenic animal models of PD, the number of adult-born neurons was decreased in the dentate gyrus (Crews et al, 2008;Marxreiter et al, 2013;Nuber et al, 2008) and a dysregulation of mood was reported (Marxreiter et al, 2013). In rodent toxin-induced models of PD, the results are inconsistent, for example, a decreased (Suzuki et al, 2010) or unchanged proliferation (Winner et al, 2009) was reported in the SGZ in a 6-hydroxydopamine (6-OHDA) rat model of PD; in a mouse model of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP), adult M A N U S C R I P T…”

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

“…However, in the OB, the amount of newly generated DA neurons is decreased in the mutant mice. More recently, the same group investigated the effect of the mutation on hippocampus plasticity and found that the survival of new hippocampal neurons is dramatically decreased in these mice [176]. The cause of this decrease in newly formed neurons has not been investigated in this model.…”

Cerebral potential biomarkers discovery and metabolic pathways analysis of α-synucleinopathies and the dual effects of Acanthopanax senticosus Harms on central nervous system through metabolomics analysis

“…The Nse is a cytoplasmatic glycolytic enzyme, an increase of whose levels is considered as a sensitive marker of neuronal damage (Schaf et al, 2005; Al-Jarrah and Jamous, 2011). Age-dependent and site-specific increase in co-localization of α-synuclein and S100b have been observed within astrocytes (Marxreiter et al, 2013). Parkinsonism also increases the expressions of Nse and S100b (Al-Jarrah and Jamous, 2011).…”