Adult neurogenesis in Parkinson’s disease

Abstract

Parkinson's disease (PD), the second most common neurodegenerative disorder, affects 1-2 % of humans aged 60 years and older. The diagnosis of PD is based on motor symptoms such as bradykinesia, rigidity, tremor, and postural instability associated with the striatal dopaminergic deficit that is linked to neurodegenerative processes in the substantia nigra (SN). In the past, cellular replacement strategies have been evaluated for their potential to alleviate these symptoms. Adult neurogenesis, the generation of new neurons within two proliferative niches in the adult brain, is being intensively studied as one potential mode for cell-based therapies. The subventricular zone provides new neurons for the olfactory bulb functionally contributing to olfaction. The subgranular zone of the hippocampus produces new granule neurons for the dentate gyrus, required for memory formation and proper processing of anxiety provoking stimuli. Recent years have revealed that PD is associated with non-motor symptoms such as hyposmia, anhedonia, lack of novelty seeking behavior, depression, and anxiety that are not directly associated with neurodegenerative processes in the SN. This broad spectrum of non-motor symptoms may partly rely on proper olfactorial processing and hippocampal function. Therefore, it is conceivable that some non-motor deficits in PD are related to defective adult neurogenesis. Accordingly, in animal models and postmortem studies of PD, adult neurogenesis is severely affected, although the exact mechanisms and effects of these changes are not yet fully understood or are under debate due to conflicting results. Here, we review the current concepts related to the dynamic interplay between endogenous cellular plasticity and PD-associated pathology.

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons

“…8), and Thy1-aSyn mice treated with TRO40303 high dose find the food reward faster compared to transgenics receiving control food (mean ± SEM time to find the buried food reward: wildtype/control: 127.1±28.81s, wildtype/TRO40303: 93.3±17.17s; Thy1-aSyn/control: 211.7±22.68s; Thy1-aSyn/TRO40303 159.5±25.81s; p<0.05 Thy1-aSyn control versus TRO40303). The mechanism of olfactory deficits in PD patients and in alpha-synuclein over-expressing mice is not known but has been related to changes in neurogenesis (Fleming et al, 2008; Hoglinger et al, 2004; Marxreiter et al, 2009; Marxreiter et al, 2013; Winner et al, 2004; Winner et al, 2008), a mechanisms that could be improved by the cholesterol oxime, independently of any effect on alpha-synuclein aggregation. Intriguingly, TRO40303 also increased the number of footslips (“errors per step”) on the challenging beam, an effect reminiscent of that induced at similar ages in Thy1-aSyn mice by dopaminergic agonists (Fleming et al, 2006).…”

Adult Neurogenesis in Neurodegenerative Diseases: Figure 1.

“…The analysis of adult neurogenesis in the different transgenic animal models of PD revealed distinct impairments of proliferative activity and survival of newly generated neurons (reviewed in Winner et al 2011;Marxreiter et al 2013). Here, we will focus on a-syn and LRRK2 models.…”

Pathological α-synuclein impairs adult-born granule cell development and functional integration in the olfactory bulb

“…It emerges that the process of integration of adult-born neurons depends on the activity of local circuits2, with extrinsic inputs critically influencing their survival134. Indeed, the deficit of both sensory and sub-cortical drives is known to disrupt the recruitment of neuronal precursors into functional assemblies5.…”