1 INTRODUCTION

Aging is the leading risk factor for Parkinson's disease (PD), the second most diagnosed neurodegenerative disorder (ND), affecting almost 1% of the population over age 60 (Blauwendraat et al., 2019). Typical neuropathological hallmarks of PD include the selective loss of dopaminergic (DAergic) cell bodies in the subtantia nigra pars compacta (SNpc) in the mesencephalon and their projections to the striatum (Str), with consequent depletion of striatal dopamine (DA), the deposition of cytoplasmic fibrillary inclusions (Lewy bodies) containing ubiquitin and α‐synuclein (α‐syn), and astroglial activation (Schapira et al., 2014). The cardinal motor signs of PD include a combination of bradykinesia, postural instability, and resting tremor. Non‐motor symptoms including hyposmia, cognitive dysfunction, and sleep and mental health disorders, often precede and/or accompany PD onset and progression, but the underlying pathological alterations in the brain are not fully understood (Reichmann et al., 2016; Schapira, Chaudhuri, & Jenner, 2017).

PD is the fastest growing ND, and because the world's population is aging the number of individuals affected is expected to grow exponentially: the number of people with PD is forecast to double from 6.9 million in 2015 to 14.2 million in 2040 (Dorsey & Bloem, 2018). Currently, most PD symptoms appear when ≥70% of the DAergic terminals are degenerated in the Str and more than half of the DA synthesizing neurons are lost in the SNpc, therefore early detection and intervention is crucial for effective neuroprotective treatment intended to prevent the degeneration of DAergic neurons and, ultimately, PD pathogenesis (Jankovic, 2019). To date, there are no effective treatments that can stop or reverse the neurodegeneration process in PD and current treatments rely on DAergic drugs, including levodopa (L‐DOPA) and DAergic agonists, which only temporarily alleviate motor symptoms (Obeso et al., 2017; Olanow, 2019; Olanow & Schapira, 2013).

Significantly, approximately 10% of PD cases can be directly attributed to genetic factors, associated with mutations in genes including α‐synuclein (SNCA), E3 ubiquitin‐protein ligase parkin (PRKN), ubiquitin C‐terminal hydrolase L1 (UCHL1), PTEN‐induced putative kinase (PINK1), DJ‐1 (PARK7), leucine‐rich‐repeat kinase 2 (LRRK2), vacuolar protein sorting 35 homolog gene (VPS35), and β‐glucocerebrosidase 1 (GBA1), linked to autosomal dominant late‐onset. In contrast, the etiology of the vast majority (up to 90%) of so called “idiopathic” PD cases is multifactorial, likely arising from a combination of polygenic inheritance and environmental exposures, with gene‐environment interactions playing a decisive role in PD onset and/or progression (Blauwendraat et al., 2019; Cannon & Greenamyre, 2013; Dzamko, Geczy, & Halliday, 2015; Guttuso, Andrzejewski, Lichter, & Andersen, 2019; Langston, 2017; Lastres‐Becker et al., 2012; L’Episcopo, Tirolo, Testa et al. 2010a; Marchetti and Abbracchio, 2005).

Aging represents the most crucial event, linking increased inflammation and oxidative stress to mitochondrial dysfunction and dysregulation of lysosomal, proteosomal and autophagic functions, likely contributing to the chronic neuronal deterioration in the PD brain (Boger, Granholm, McGinty, & Middaugh, 2010; Dzamko et al., 2015; Giguère, Burke Nanni, & Trudeau, 2018; Marchetti & Abbracchio, 2005; McGeer & McGeer, 2008; Nguyen et al., 2019; Surmeier, 2018). Hence, with advancing age, the nigrostriatal DAergic system progressively declines and the adaptive/compensatory DAergic potential gradually fails, leading to the slow but inexorable nigrostriatal degeneration of PD with the late appearance of clinical signs (Bezard & Gross, 1998; Collier et al., 2007; de la Fuente‐Fernández et al., 2011; Hindle, 2010; Hornykiewicz, 1993; Obeso et al., 2017).

A cardinal feature of aging and PD is the diminishment of adult neurogenesis, an active process present in most mammalian species including humans whereby new neurons are generated throughout life from neural stem/progenitor cell (NSC) activation within their specialized neurogenic niches (Apple, Solano‐Fonseca, & Kokovay, 2017; Bond, Ming, & Song, 2015; Chandel, Jasper, Ho, & Passegué, 2016; Gage, 2000; Ming & Song, 2005; Winner, Desplats, et al., 2009a). NSCs are self‐renewing, multipotent and undifferentiated precursor cells that have the ability to differentiate into glial and neuronal lineages. In physiological conditions, only two specific areas, i.e. the subventricular zone (SVZ) lining the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus (Figure 1), can produce new neurons, with the potential to support odour discrimination, spatial learning, and contextual memory capabilities (Alvarez‐Builla, Garcia‐Verdugo, & Tramontin, 2001; Eriksson et al., 1998; Fuentealba, Obernier, & Alvarez‐Buylla, 2012; Gage, 2000; Spalding et al., 2013). In both regions slowly dividing quiescent NSCs give rise to activated NSCs, which rapidly differentiate into transit‐amplifying progenitor cells (TAPs) and subsequently into immature neurons (Encinas et al., 2011; Obernier et al., 2018). Early impairment of SVZ and hippocampal SGZ neurogenesis is implicated in PD‐associated pre‐motor symptoms, which may in turn contribute critically to the disease process (Agnihotri et al., 2019; Lim, Bang, & Choi, 2018; Titova et al., 2017; Winner & Winkler, 2015).

Figure 1 Open in figure viewer PowerPoint 1999 1997 2011 +) neuroblasts in red, and dividing, bromodeoxyuridine‐positive (BrdU+) NSCs in green, are seen forming chains traveling along the RMS to the OB where they become granular and periglomerular interneurons involved in odor discrimination. Magnifications of DCX+/BrdU+ NSCs are shown in the boxed areas The subventricular (SVZ) and the subgranular (SGZ) zones of the adult rodent brain. (a) Sagittal brain section showing the subventricular zone (SVZ) lining the lateral ventricles (LV) and the adjacent striatum (Str), and the hippocampal subgranular zone (SGZ). In blue the trajectory of migrating neuroblasts along the rostral migratory stream (RMS) reaching the olfactory bulb (OB); in red, the CA1 field of the hippocampus and the SGZ in the dentate gyrus (DG) are shown. (b, c) Schematic representation of the neurogenic regions in the adult brain. The SVZ niche (b) composed of SVZ astrocytes (type B1 cells), rapidly proliferating (type C) cells, migrating neuroblast (type A cells), which migrate through the RMS to the OB, and ependymal cells (type E cells) (Doetsch et al.,). In the SGZ, radial glia‐like precursors (RGLs) within the SGZ serve as one type of quiescent NSCs (type 1 cells) and continuously give rise to both DG neurons and astrocytes (Bonaguidi et al.,). Mature granule neurons then migrate into the granule cell layer (GCL). (d) A sagittal reconstruction of dual immunofluorescent stained images by confocal laser scanning microscopy. SVZ‐migrating doublecortin‐positive (DCX) neuroblasts in red, and dividing, bromodeoxyuridine‐positive (BrdU) NSCs in green, are seen forming chains traveling along the RMS to the OB where they become granular and periglomerular interneurons involved in odor discrimination. Magnifications of DCX/BrdUNSCs are shown in the boxed areas

Adult neurogenesis is activated by various brain injuries, generating new neurons that migrate along the blood vessels toward an injured area where they may repair damaged tissue (Kojima et al., 2010; Yamashita et al., 2006). NSCs residing in the adult human SVZ may generate neurons that migrate to the Str, rather than into the olfactory bulb (Ernst et al., 2014). Otherwise “dormant” NSC subpopulations can be activated under specific CNS injuries and via cell‐specific signalling mechanisms (Llorenz‐Bobadilla et al., 2015). After pathological stimulation, neuroprogenitors can be activated in regions otherwise considered to be non‐neurogenic, such as the Str (Bedard, Cossette, Levesque, & Parent, 2002; Dayer, Cleaver, Abouantoun, & Cameron, 2005; Inta, Cameron, & Gass, 2015; Luzzati et al., 2011; Nato et al., 2015), while the presence of neurogenesis in the SN still remains a matter of debate (Arzate, Guerra‐Crespob, & Covarrubiasa, 2019; Barker, Götz, & Parmar, 2018; Farzanehfar, 2018; Klaissle et al., 2012; L'Episcopo et al., 2014a; Lie et al., 2002; Xie et al., 2017).

Evidence is available that quiescent neuroprogenitors reside in the tegmental aqueduct periventricular region (Aq‐PVRs), which is close to the SNpc and harbors clonogenic NSCs endowed with DAergic potential (Hermann et al., 2006, 2009; Hermann & Storch, 2008; L'Episcopo et al., 2011a). Additionally, adult Aq‐PVR NSCs can be activated and induced to differentiate into DAergic neurons, both in vitro and after PD injury in vivo (Hermann et al., 2006, 2009; Hermann & Stork, 2008; L'Episcopo et al., 2011a, 2014a; L'Episcopo, Tirolo, Peruzzotti‐Jametti, et al., 2018a; Xie et al., 2017).

The therapeutic relevance of endogenous neurogenesis for the recovery of the injured brain and, particularly, the aged PD brain, is being actively investigated, yet remains to be elucidated (van den Barker et al., 2018; Kempermann et al., 2018; Le Grand, Gonzalez‐Cano, Pavlou, & Schwamborn, 2015; Neves et al., 2017; van den Berge et al., 2013). This avenue of research is particularly significant in light of the dramatic decline of NSC neurogenic potential in PD brain during aging and neurodegeneration, likely underlying the age‐dependent cognitive deficits and the failure to replace or repair dysfunctional or dead neurons (Anacker & Hen, 2017; Katsimpardi & Lledo, 2018; Kemperman et al., 2018; Seib & Martin‐Villalba, 2015; Takei, 2019).

The question therefore arises as to whether it is possible to counteract these age‐dependent and region‐specific restrictive mechanisms inhibiting DAergic plasticity, in order to re‐activate the endogenous neurorepair and regeneration programs in the aged PD brain. In the last decade, we have explored the functional role of adult neurogenesis in PD by addressing the molecular and cellular NSC regulatory mechanisms underlying the age‐dependent decline of neurogenic potential in a 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine/1‐methyl‐4‐phenylpyridinium (MPTP/MPP+)‐induced rodent model of basal ganglia injury, investigating the potential to stimulate adult neurogenesis as a means to support neuroprotective and neurorestorative therapies (L'Episcopo, Serapide, et al., 2011b; L'Episcopo et al., 2011a, 2013, 2012, 2014a; L'Episcopo, Tirolo, Serapide, et al., 2018a, 2018b; Marchetti, 2018; Marchetti et al., 2013; Marchetti & Pluchino, 2013). Particularly, we concentrated on the key pathway regulating DAergic neurogenesis, from neurodevelopment through aging and neurodegeneration: the wingless‐type mouse mammary tumor virus integration site (Wnt)/β‐catenin (WβC) signalling cascade (Brodski, Blaess, Partanen, & Prakash, 2019; Inestrosa & Arenas, 2010; Maiese, 2015; Maiese, Faqi, Chong, & Shang, 2008; Marchetti, 2018; Nusse & Clevers, 2017; Nusse & Varmus, 1982; Palomer et al., 2019; Salinas, 2012; Tapia‐Rojas & Inestrosa, 2018; Toledo et al., 2017; Wurst & Prakash, 2014). The WβC‐signalling pathway is of utmost importance owing to its ability to promote tissue repair and regeneration of stem cell activity in diverse organs, and in light of its crucial role in age‐related pathogenesis and therapy of disease (Banerjee, Jothimani, Prasad, Marotta, & Pathak, 2019; Garcìa, Udeh, Kalahasty, & Hackam, 2018; Garcìa‐Velasquez & Arias, 2017; Nusse & Clevers, 2017; Tauc & Jasper, 2019; Toledo et al., 2019). The hallmark of the WβC‐pathway is the activation of the transcriptional activity of β‐catenin, the pivotal mediator of the so‐called “canonical” Wnt signalling. In this system, Wnt's binding to its cell surface receptors triggers a complex cascade of molecular events leading to the cytoplasmic accumulation of β‐catenin, which enters the nucleus, and associates with T‐cell factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors, in turn promoting the transcription of Wnt target genes involved in a diversity of NSC functions, including survival, proliferation, and differentiation (Adachi et al., 2007; Brodski et al., 2019; Kalani et al., 2008; Piccin & Morshead, 2011). WβC‐signalling positively regulates adult neurogenesis in both the SVZ and SGZ at multiple levels: from activation of stem cells to neuronal differentiation (as reviewed by Hirota et al., 2016; Ortiz‐Matamoros et al., 2013; Varela‐Nallar & Inestrosa, 2013).

Wnts and the components of WβC‐signalling are not only widely expressed in the adult SVZ and ventral midbrain (VM), but most importantly they respond to MPTP injury and are required to trigger neurorepair programs in MPTP‐induced PD thanks to a “Wnt crosstalk dialogue” with glial cells (L'Episcopo et al., 2011b, 2011a, 2012, 2013; Marchetti et al., 2013). The critical role of astrocyte‐derived Wnt1 and WβC‐signalling was further shown in the Aq‐PVR DAergic niche, where WβC controls the fate specification of adult DAergic precursors (L'Episcopo et al., 2014a, 2014b). Conversely, aging‐dependent oxidative stress and inflammatory pathways correlate with a downregulation of WβC ‐signalling in NSC niches and a dramatic up‐regulation of endogenous Wnt‐antagonists, with implications for SVZ neurogenesis, Aq‐PVR‐NSC activation, and DAergic self‐repair ability (L'Episcopo et al., 2012, 2013, 2014a; L'Episcopo, Tirolo, Serapide, et al., 2018a, 2018b; Marchetti et al., 2013). In 2013, these findings inspired the perspective, “Wnt your brain be inflamed? Yes, it Wnt!” (Marchetti & Pluchino, 2013), summarizing the potential role of an inherent self‐protective “Wnt‐glial” connection in the context of major NDs. Strikingly, the WβC‐pathway plays a critical role during development, in adult and aging SVZ‐, Aq‐PVR‐ and SGZ‐niches, thus providing a robust homeostatic regulatory mechanism for NSC survival, proliferation, differentiation and integration, and bearing the potential to respond to injury and regeneration with potential consequences for both non‐motor‐ and motor‐related features of PD.

Owing to the potential associations between the Wnt pathway and mitochondrial dynamics, apoptosis, and the cell cycle, which in turn affect NSC self‐renewal and differentiation (Beckervordersandforth, 2017; Beckervordersandforth et al., 2017; Chandle et al., 2016; Chong, Shang, Hou, & Maiese, 2010; Rasmussen et al., 2018; Richetin et al., 2017; Singh, Mishra, Bharti, et al., 2018b; Walter et al., 2019), we herein highlight the role of WβC‐signalling and its crosstalk with astrocyte‐ and microglial‐derived oxidative and inflammatory pathways in the regulation of adult neurogenesis in PD. Particular attention is paid to the exacerbated inflammation and oxidative stress associated with the upregulation of endogenous Wnt‐inhibitors.

Summarizing our work within this context, we propose a dual‐hit hypothesis governing NSC downmodulation and failure to repair. The mechanisms underlying these phenomena constitute a synergy between (a) the upregulation of proinflammatory glial pathways, (b) the decline of anti‐oxidant self‐defence mechanisms, such as the nuclear factor erythroid‐2‐related factor 2 (Nrf2)‐heme oxygenase 1 (Hmox1) axis, a key mediator of cellular adaptive response, and (c) the decline of astrocyte‐derived Wnts leading to NSC neurogenic impairment, with a consequent failure to recover from a PD insult. As a result, both pharmacological and cellular therapies involving the up‐regulation of WβC‐signalling and immunomodulation were reported to ameliorate the aged microenvironment, thereby promoting endogenous neurogenesis, ultimately boosting a full neurorestoration program in the aged PD brain (L'Episcopo et al., 2011c, 2012, 2013; L'Episcopo et al., 2014a; L'Episcopo, Tirolo, Serapide, et al., 2018a, 2018b; Marchetti, 2018; Marchetti et al., 2013; Marchetti & Pluchino, 2013). While little is known on WβC‐signalling in the PD‐injured hippocampus, it seems plausible that a comparable dysfunction of the WβC‐pathway may well be at play in the SGZ of the DG, with potential consequences for hippocampal neurogenesis in PD and its involvement in non‐motor symptoms of PD.

Corroborating our earlier findings, a number of recent studies have highlighted the critical importance of WβC crosstalk with survival and inflammatory pathways in inciting neurogenesis and neurorepair (Chen et al., 2018; Kalamakis et al., 2019; Kase, Otsu, Shimazaki, & Okano, 2019; Mishra et al., 2019; Morrow & Moore, 2019; Ray et al., 2018; Singh, Mishra, Bharti, et al., 2018b; Singh, Mishra, Mohanbhai, et al., 2018a; Singh, Mishra, & Shukla, 2016).

Herein, after a description of the key Wnt‐signalling components and a synopsis of adult neurogenesis in PD, we will focus on the role of WβC‐signalling as a common final pathway in mediating NSC regulation, from development to aging and PD degeneration. We aim to survey recent literature in the field supporting the upregulation of WβC as a means to re‐activate neurogenesis and incite regeneration in the injured brain, particularly in the context of modalities through which the inherent self‐repair capacities of the aged PD brain, can be engaged (Chen et al., 2018; Kase et al., 2019; Kaur, Saunders, & Tolwinski, 2017; Mishra et al., 2019; Zeng et al., 2019; Zhao, et al., 2018; Zhang et al., 2018a, 2018b, 2018ca,b,c; and following sections).