Neural stem cells of the subventricular zone: A potential stem cell pool for brain repair in Parkinson's disease

Abstract

Parkinson's disease is a neurodegenerative disease caused by the degeneration of dopaminergic neurons in the substantia nigra. There are no curative treatments, and therefore, there is an urgent need for new approaches. One potential strategy being investigated is stem cell-based approaches to replace lost neurons, by, for example, harnessing endogenous neural stem cells (NSCs). These cells are found in the subventricular zone (SVZ) aligning the lateral ventricles and remain in a dormant state in the aged and diseased mammalian brain. However, with the appropriate stimuli, NSCs can shift into an activated state, proliferate, and differentiate. In this review, we discuss how PD pathology affects the behavior of NSCs and current pharmacological strategies to boost regeneration in PD. NSCs of the SVZ could be a stem cell source for brain repair, and future studies should shed light on whether these stem cells have the potential to produce functional neuronal cells.

Keywords: Parkinson’s disease; adult neurogenesis; neural stem cells; stem cell-based therapy; subventricular zone.

Graphical abstract

Figure 1

Clinical and neuropathological features of Parkinson’s disease Parkinson’s disease is characterized by motor and non-motor symptoms. The disease is caused by a progressive loss of dopaminergic neurons in the substantia nigra, which leads to dopamine deficiency in the nigrostriatal pathway. Other neuropathological hallmarks are the intracellular Lewy bodies containing alpha-synuclein and a neuroinflammatory response mediated by microglia and astrocytes. Created with BioRender.com.

Figure 2

Schematic overview of the human SVZ (A) Sagittal view of the human brain with the lateral ventricle in green, the striatum in purple , and the substantia nigra in orange. (B) Coronal section of the human brain at the level of the basal ganglia with a detailed overview of the subventricular zone. A layer of ependymal cells aligns the lateral ventricle, which is followed by a hypocellular gap devoid of cell nuclei. The subventricular zone consists of neural stem cells (NSCs), neural progenitor cells (NPCs), oligodendrocyte progenitor cells (OPCs), neuroblasts, astrocytes, microglia, oligodendrocytes, and blood vessels (BVs). Created with BioRender.com.

Figure 3

Differences between active and quiescent neural stem cells With aging, neural stem cells (NSCs) transition from an active to a quiescent state. Active NSCs are characterized by proliferation, activation of the Egfr and Wnt pathways, expression of Egfr and Nestin, and a highly active lysosomal pathway. In contrast, quiescent NSCs do not proliferate, and the Bmp-4 and Notch signaling pathways are activated. Quiescent NSCs lack the expression of Egfr and Nestin but do express the cell cycle inhibitor P57. Additionally, aging reduces the activity of the lysosomal pathway in quiescent NSCs. Egfr, epidermal growth factor receptor; Bmp-4, bone morphogenetic protein 4; Fgf-2, fibroblast growth factor 2. Created with BioRender.com.

Figure 4

Pathological hallmarks of Parkinson’s disease that affect adult neurogenesis (A) NSCs express both D2 and D3 dopamine receptors. Dopamine stimulates NSC proliferation, which is partially mediated via Egf. Degeneration of dopaminergic neurons in the substantia nigra leads to dopamine deficiency in the nigrostriatal pathway. Rodent models of dopaminergic neuron loss show conflicting results on the proliferative capacity of NSCs. This apparent contradiction could be explained by differences in the severity of neuronal loss, BrdU paradigm used, how long after induction of neuronal loss the proliferative capacity of NSCs was assessed, and the region of the SVZ that was analyzed. It has yet to be determined whether these pathological hallmarks also affect adult neurogenesis in patients with PD. (B) Three genes that carry mutations that can increase the risk of developing PD are LRRK2, PARK2, and VPS35. LRRK2 interacts with several components of the Wnt/β-catenin pathway, and mutations in LRRK2 have been shown to decrease the proliferative capacity and differentiation capacity of NSCs. VPS35 regulates Wnt signaling and decreases LRRK2 kinase activity and might therefore affect proliferative and differentiation capacity of NSCs. PARK2 is an E3 ubiquitin ligase, and two of its targets are p21, a cell cycle inhibitor, and β-catenin, a component of the Wnt pathway. It is likely that mutations in PARK2 affect the proliferative capacity of NSCs. However, this has yet to be determined. (C) Accumulation of monomeric alpha-synuclein into fibrils is a key hallmark of PD. In vivo, overexpression of wild-type alpha-synuclein leads to the reduction in differentiation capacity of NSCs in the rodent SVZ, while the pathological A53T also affects the proliferative capacity of NSCs. In vitro, it has been shown that this effect is mediated through the Notch pathway. LRRK2, leucine-rich repeat kinase 2; PARK2, Parkin RBR E3 ubiquitin protein ligase 2; Egf, epidermal growth factor. Created with BioRender.com.

Figure 5

Strategies to boost neurogenesis as a therapeutic approach for Parkinson’s disease The capacity of NSCs to proliferate and self-renew can be stimulated through different strategies (left). Growth factors such as Cdnf, Lgf, and Fgf together with Egf enhance proliferation of NSCs in the SVZ. P21 is a negative regulator of the cell cycle, and intranasal administration of GD3 inhibits p21 thereby stimulating proliferation. As NSCs express several dopamine receptors, increasing the dopamine concentration in the brain with medication, such as quinpirole, pramipexol, levodopa, or selegiline was shown to stimulate proliferation of NSCs. For therapeutic relevance, NSCs need to differentiate into dopaminergic neurons (right). The Wnt pathway is important for neuronal development, and stimulating Wnt signaling via inhibition of Gsk-3β can stimulate NSC self-renewal as well as differentiation. Ganglioside GM1 improves NSC differentiation through Nurr1 and Gdnf. Besides Gdnf, Bdnf, another growth factor, also stimulated differentiation. Cdnf, cerebral dopamine neurotrophic factor; Lgf, liver growth factor; Fgf, fibroblast growth factor ; Egf, epidermal growth factor; p21, cyclin-dependent kinase inhibitor 1A; Gsk-3β, glycogen synthase kinase-3 beta; Nurr1, nuclear receptor-related 1; Gdnf, glial cell-derived neurotrophic factor; Bdnf, brain-derived neurotrophic factor. Created with BioRender.com.