Neuroglial Senescence, α-Synucleinopathy, And The Therapeutic Potential Of Senolytics in Parkinson's Disease Part 1

INTRODUCTION

Parkinson's disease (PD) is the most common neurodegenerative disease that is primarily associated with the loss of motor function. It is also the second most prevalent neurodegenerative disease besides Alzheimer's disease. 

In recent years, research has shown an inextricable relationship between exercise and memory. As the pace of people's daily lives accelerates and they are in high-intensity work and study environments, many people gradually ignore the importance of sports. Moreover, lack of sports not only affects physical health but also hurts memory.

First, let's look at the relationship between exercise and brain and memory health. Normally, the human brain produces neurons, which are cells that carry signals throughout the body. The connections between neurons make up our memory system. Because memories are stored in the connections and communications between many neurons, the brain is complex, and any factor that affects neurons, including lifestyle, diet, sleep, and exercise, has the potential to affect our brain function.

Secondly, from a physiological point of view, exercise helps to maintain the health of the human body and promote blood circulation. During exercise, a large amount of oxygen and nutrients are transported to the brain through the blood, which is very beneficial to brain health. At the same time, exercise can release endorphins in the body, which is a neurotransmitter that can improve mood and reduce anxiety, which is very beneficial to improving people's memory, concentration, and creativity.

Finally, a large-scale study found that as long as you exercise for at least 150 minutes per week, you can effectively improve memory and learning efficiency. In addition, a variety of sports such as swimming, running, mountain climbing, cycling, dancing, etc. can stimulate the human brain and are very beneficial to improving memory.

Therefore, we must firmly believe in the wonderful relationship between exercise and memory, pay attention to the positive impact of exercise on the brain, and actively advocate and practice a healthy lifestyle to achieve dual health of the body and brain. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

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Although PD is considered primarily a movement disorder, it can present with severe non-motor symptoms such as impaired bladder control, sleep disturbances, emotional disturbances, and constipation. 

The risk for PD increases with age, male gender, pesticide exposure, and melanoma (Chen et al., 2017; Delamarre and Meissner, 2017; Ye et al., 2020). Conversely, PD risk has an inverse relationship with nicotine use, caffeine intake, and urate levels (Chen et al., 2013; Bakshi et al., 2015; Delamarre and Meissner, 2017; Marras et al., 2019). 

Several gene mutations have been associated with increased risk. Familial PD is linked to such genes as SNCA, PRKN, LRRK2, PINK1, FBX07, PLA2G6, and others (Blauwendraat et al., 2020). Sporadic PD cases have been associated with genetic mutations in genes such as GBA, ACMSD, STK39, NMD3, STBD1, GPNMB, FGF20, MMP16, STX1B, ITGA8, and others (Chai and Lim, 2013). 

The underlying pathophysiology of PD is linked to oxidative stress and inflammation (Hald and Lotharius, 2005; Chen et al., 2018). Recent and compelling discussions have also highlighted the role of lipidopathy in PD pathology (Fanning et al., 2020). However, proteinopathy is the pathological hallmark of the disease, as it is in many neurodegenerative diseases.

The primary focus of neurodegenerative pathophysiology has been historically centered on the role of misfolded pathogenetic proteins. For example, amyloid-beta peptides are implicated in Alzheimer's disease, TAR DNA-binding protein 43 is implicated in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, the huntingtin protein is implicated in Huntington's disease, and α-synuclein is implicated in PD (Arrasate and Finkbeiner, 2012; Halliday et al., 2012; Stefanis, 2012; Blokhuis et al., 2013; Cheignon et al., 2018). 

Furthermore, many neurodegenerative diseases involve aggregation of the tau protein, including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and PD (Spillantini and Goedert, 2013; Eftekharzadeh et al., 2018). 

Aging is the greatest risk factor for developing PD (Reeve et al., 2014). The nine classic hallmarks of cellular aging include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and finally, altered intercellular communication, which is linked to chronic inflammation (López-Otín et al., 2013). 

The Geroscience Hypothesis identifies the following seven "pillars of aging": macromolecular damage, epigenetics, inflammation, adaptation to stress, proteostasis, stem cells and regeneration, and metabolism (Kennedy et al., 2014). 

Senescent cells are intrinsically linked to the aging process. The senescence-associated secretory phenotype (SASP) of senescent cells releases pro-inflammatory cytokinesand, and chemokines, and promotes inflammation (Coppé et al., 2008). The recently developed Unitary Theory of Fundamental Aging Mechanisms describes the cellular facets of aging as being so closely interrelated that therapeutic targeting of one aspect, such as cellular senescence, might mitigate many, or all, of the others (Tchkonia et al., 2021). 

Furthermore, the Unitary Theory of Fundamental Aging Mechanisms identifies several other additional aging-related hallmarks such as increased fibrosis, increased CD38, decreased NAD+, and the accumulation of misfolded and aggregated proteins (Tchkonia et al., 2021). Operating under the Unitary Theory of Fundamental Aging Mechanisms, a direct relationship should exist between senescent cells and proteinopathy. 

Since most of the research conducted on senescent cells has focused on peripheral tissues, it is especially of interest to explore the relationship between senescent cells and proteinopathy in the central nervous system (CNS) (Baker and Petersen, 2018). Here, we explore the relationship between αsynucleinopathy, senescent astrocytes, and senescent microglia in PD. Additionally, the potential of analytics for therapy in PD will be discussed.

α-SYNUCLEINOPATHY IN PARKINSON'S DISEASE

The protein α-synuclein is small (14 kDa), soluble, intrinsically unstructured, and encoded by the SNCA gene (Uversky, 2003). The intrinsically disordered nature of monomeric αsynuclein is stable and conserved across mammalian cell types (Theillet et al., 2016). α-synuclein is located ubiquitously in CNS presynaptic terminals (Jakes et al., 1994). 

Although the normal function of α-synuclein is not well understood, it is known to be involved in some regulatory roles such as neurotransmitter release and synaptic plasticity, dopamine metabolism, membrane remodeling, and DNA repair (Bendor et al., 2013; McCann et al., 2014; Schaser et al., 2019). The most common α-synuclein isoform found in humans is 140 amino acids long (Jakes et al., 1994; Goedert et al., 2017). 

Under normal physiological conditions, the structure of α-synuclein resists aggregation. The N-terminal region is amphipathic, has a basic pH, binds to membranes, and changes from a disordered structure to an α-helical structure when bound to lipids (Bartels et al., 2010, 2011; Theillet et al., 2016). The N-terminal region spans the first 60 residues of αsynuclein and is the location of three familial PD mutations: A30P, E46K, and A53T (Ono, 2017). 

The N-terminal region also includes the beginning of a stretch of seven imperfect repeats of "KTEKEGV" (Dettmer et al., 2015). N-terminal acetylation destabilizes α-synuclein, increases α-synuclein levels, and enhances α-synuclein toxicity (Vinueza-Gavilanes et al., 2020). The central core spans from residues 61 to 95 and consists of hydrophobic amino acids. 

The central region is also referred to as the non-amyloid-β component (NAC) and is the site essential for misfolding and aggregation (Ono, 2017). In wild-type α-synuclein, the NAC is protected from cytoplasmic exposure due to long-range interactions between the N-terminal and the C-terminal, which acts to prevent aggregation (Bertoncini et al., 2005; Theillet et al., 2016). 

Additionally, chaperones are known to bind to the N-terminus around tyr39, which further helps to prevent aggregation (Burmann et al., 2020). Mutations in the N-terminal have been shown to disrupt the interaction between the N-terminal and the C-terminal to promote the pathological gain-of-function αsynuclein aggregation (Bertoncini et al., 2005). 

The remainder of the imperfect "KTEKEGV" repeated motifs are found in the NAD region. The C-terminal is intrinsically disordered and is highly acidic (Suzuki et al., 2018). The structure of α-synuclein is depicted in Figure 1. 

The SNCA gene in humans has a chromosomal location of 4q22.1, a length of 114,226 base pairs, and contains six exons (Touchman et al., 2001). SNCA transcription is regulated by beta-2-adrenoreceptor (B2AR), which can be antagonized to increase the risk of PD or activated to reduce the risk of PD (Mittal et al., 2017). 

The cellular distribution patterns of various SNCA transcript quantities among humans and mice are shown in Figure 2. The first genetic mutation identified to be associated with PD is the G-to-A transition at the 209th nucleotide, which results in the A53T mutation of the SNCA gene located between the 4th and 5th repeat of KTEKEGV (Goedert, 1997; Polymeropoulos et al., 1997; Stefanis, 2012). 

The familial and highly penetrant A53T mutation is inherited in an autosomal dominant manner and is associated with wearly-onsetnset PD (Puschmann et al., 2009). 

In rat dopaminergic PC12 cells, the A53T mutation has been shown to induce α-synuclein related cell death due to reduced proteasome activity, increased reactive oxygen species (ROS), increased mitochondrial permeability and dysfunction, cytochrome C release, increased activity of caspase3, caspase-9, and caspase-12, and finally, endoplasmic reticulum (ER) stress due to α-synuclein accumulation in the ER (Tanaka et al., 2001; Smith et al., 2005; Colla, 2019). Sequence mutations in the SNCA gene, such as A53T, are known to increase the rate and magnitude of α-synuclein aggregationAfterto intracell α-synuclein aggregation, dopamine accumulates in the cytoplasm, sm, and dopaminergic toxicity increases in severity (Tabrizi et al., 2000). 

Duplications or triplications of wild-type SNCAares are also implicated in PD pathology, PD with dementia, dementia with Lewy bodies, and multiple system atrophy (Book et al., 2018). 

SNCA triplication is linked to early onset autosomal dominant familial PD and PD-related dementia, as demonstrated in the Spellman-Muenter kindred, a Swedish-American family, a family from Italy, and several others (Singleton et al., 2003; Farrer et al., 2004; Olgiati et al., 2015; Zafar et al., 2018). Human carriers of the triplicate mutation of SNCA had twice the control levels of α-synuclein mRNA in blood and brain tissue (Miller et al., 2004). 

Soluble α-synuclein protein levels were also doubled in the blood of the triplicate SNCA carriers, whereas the genomic triplication of SNCA led to greater levels of insoluble α-synuclein aggregates in the brain (Miller et al., 2004). 

DA neurons differentiated from human induced pluripotent stem cells (hiPSCs) from a PARK4 patient who also had SNCA triplication showed increased levels of α-synuclein compared to control hiPSC-derived DA neurons (Fukusumi et al., 2021). 

Genomic duplication of SNCA also increases α-synuclein levels and is causal for familial PD (Chartier-Harlin et al., 2004; Ibáñez et al., 2004). There is well well-established direct relationship between SNCA copy number,α-synuclein abundance, and PD phenotype severity (Singleton and Gwinn-Hardy, 2004). In contrast to triplication, cases of SNCA duplication resemble idiopathic PD with a late onset, and slow progression, and are spared from dementia (Chartier-Harlin et al., 2004; Ibáñez et al., 2004). 

However, there has been a single case described recently of a male with SNCA duplication who developed early-onsetPD with aggressive progression and rapid cognitive decline (Kielb et al., 2021). The abnormal accumulation of phosphorylated α-synuclein into insoluble aggregate is characteristic of Lewy bodies and Lewy neurites and is the defining histopathological hallmark of α-synucleinopathies. 

The three main α-synucleinopathy diseases include PD, Lewy Body Dementia (LBD), and multiple system atrophy (MSA) (McCann et al., 2014). The most common αsynucleinopathy disease is PD (Grazia and Goedert, 2000). 

Lewy neurites mostly have a course, thin, and elongated appearance (Braak et al., 1999). They are located in the cytoplasm and are greater in number than Lewy bodies, especially in the striatum and amygdala (Volpicelli-Daley et al., 2014). They are also heavily distributed in the dorsal vagal nucleus, the CA2/3 hippocampus region, and the nucleus basalis of Meynert (Kon et al., 2020). 

Lewy neurites have been shown to impair the axonal transport of autophagosomes and endosomes that contain Rab7 and TrkB receptors (Volpicelli-Daley et al., 2014). Lewy bodies are well-defined, spherical protein conglomerates composed of misfolded α-synuclein and other components. They are present in PD patients except for a handful of unique familial cases (Johansen et al., 2018). 

Lewy bodies are located in the neuronal cytoplasm and are found distributed across the brain stem, limbic areas, and neocortical brain regions (Rezaie et al., 1996; Spillantini and Goedert, 2000). Lewy body accumulation correlates with aging, and the severity of Pthethe d severity of dementia (Saito et al., 2004). Likewise, α-synuclein in Lewy bodies is phosphorylated and nitrated, indicating oxidative stress is intrinsic to their formation (Giasson et al., 2000; Foulds et al., 2011; McCormack et al., 2012; Wang et al., 2012; Kellie et al., 2014). 

Although widely recognized as contributing to neurodegeneration, there is some debate over whether Lewy bodies serve a protective role in the cell, if the process of forming the Lewy body promotes neurodegeneration, or if the Lewy body itself promotes neurodegeneration (Ono, 2017; Iqbal et al., 2020; Mahul-Mellier et al., 2020). All three of these hypotheses are likely partially true. 

Furthermore, Lewy body composition has received renewed attention recently, where the role of both α-synuclein and α-synuclein components are being reassessed. Some α-synuclein components of interest include ubiquitin, damaged organelles such as fragmented mitochondria, and lipids (Nakamura et al., 2011; Lashuel, 2020). 

It is important to note that there is evidence to suggest that α-synuclein is not the most abundant constituent of Lewy bodies, contrary to the filament-centric dogma (Lashuel, 2020). Misfolded proteins in neurodegenerative diseases have been shown to exist both intracellularly and extracellularly (Peng et al., 2020). In PD, α-synuclein aggregations are seen earliest in the disease progression to be located in the olfactory bulb and the dorsal motor nucleus of the tenth cranial nerve (Peng et al., 2020; Wakabayashi, 2020). 

The pathological α-synuclein then spreads rostrally through the brainstem, midbrain, forebrain, and eventually to the cortex (Braak and Del Tredici, 2017). αsynuclein has been shown to pass between neurons, from neurons to microglia, from neurons to astrocytes, between astrocytes, and across the blood-brain barrier (BBB) (Fellner et al., 2013; Loria et al., 2017; Rostami et al., 2017; Bogale et al., 2021).

Microglial α-Synucleinopathy in Parkinson's Disease

Microglia are the CNS's resident immune macrophage that monitors for homeostatic threats and intervenes when necessary. Along with other glial populations, microglia are highly diverse based on their neuroanatomical location and functional plasticity, suggesting that they are influenced by local environment cues (Olah et al., 2011; Bachiller et al., 2018; Li and Barres, 2018; Kam et al., 2020). 

For example, microglia in healthy mouse basal ganglia regions had region-specific morphology, cell density, and count, lysosome content and distribution, membrane resting potentials, and transcriptomes (De Biase et al., 2017; Costa et al., 2021). 

Additionally, microglia experience altered intracellular α-synuclein levels based on their environment, such as in response to cytokines or cerebrospinal fluid (CSF) from PD patients (Bick et al., 2008; Schiess et al., 2010). 

Substantia nigra pars compacta (SNpc) microglia differ from microglia in the ventral tegmental area (VTA) (Shaerzadeh et al., 2020). Perhaps regional microglial differences might partly explain the PD-related loss of dopaminergic neurons in the SNpc, rather than in the VTA. The reasons for this regional selectivity of dopaminergic neuronal loss are not yet fully understood (Krashia et al., 2019; Shaerzadeh et al., 2020). 

However, it seems like a reasonable hypothesis that microglial activation has a role to play. For example, mice overexpressing wildtype human α-synuclein throughout the CNS had increased levels of activated microglia and TNF-alpha in the striatum as early as 1 month old and then the substantia nigra as early as 5 months old, but not in other brain areas (Watson et al., 2012). 

The region-specific activated microglial response to increased levels of α-synuclein persisted as long as monitoring took place, over 14 months (Watson et al., 2012). In human PD patients, PET imaging and postmortem brain analysis showed regionally activated microglial cells in the midbrain, the frontal cortex, and the temporal cortexes (Gerhard et al., 2006; Garcia-Esparcia et al., 2014). 

Both 1-Methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) and α-synuclein over-expression models of PD in monkeys also showed region-specific and long-term microglial activation in the SNpc (Kanaan et al., 2008; Barkholt et al., 2012). 

Therefore, elevated α-synuclein levels cause microglia to become quickly and persistently activated, which leads to increased neuroinflammatory secretions from the microglia.

Among in vitro and in vivo models of PD, α-synuclein causes microglia to become rapidly activated, to migrate to the α-synuclein source and then increases phagocytic and proinflammatory activity (Zhang et al., 2005; Su et al., 2008; Wang et al., 2015; Mavroeidi and Xilouri, 2021). 

Extracellular αsynuclein is cleared through activated microglial engulfing and autophagy, mediated by TLR4-NF-kB signaling in a process recently discovered and coined as "synucleinphagy" (Choi et al., 2020). 

However, microglial phagocytic activity is reduced with age (Bliederhaeuser et al., 2016). The level of microglial activation is greater in the presence of α-synuclein mutants compared to wild-type α-synuclein protein, perhaps reflecting the severity of their respective associated pathologies (Roodveldt et al., 2010; Hoenen et al., 2016). 

Indeed, the PD-related α-synuclein A53T mutation has been shown to increase the production of microglial CXCL12 in cell culture and mouse SNpc (Li et al., 2019). Postmortem brain tissue of PD patients has also shown a direct correlation between α-synuclein and CXCL12 levels (Li et al., 2019).

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