Exosomes for the Treatment of Parkinson’s Disease

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1		David J Rademacher	--	1793	2023-05-04 16:52:18	\|
2	format correct	Jessie Wu	+ 1 word(s)	1794	2023-05-05 04:58:39	\|

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11041187

Extracellular vesicles (EVs) are membrane-enclosed particles released by cells into the extracellular space. EVs can be classified as exosomes (EXs), microvesicles, or apoptotic bodies based on their origin and size. EXs are enclosed within a single phospholipid bilayer, secreted by all cell types, formed by the inward invagination of the endosomal membrane and fusion of the multivesicular body (MVB), and are typically 30–150 nm in diameter. Microvesicles are EVs that form from direct outward budding from the cell’s plasma membrane and are typically 100 nm to 1 µm in diameter. Pathogenic forms of α-synuclein (α-syn) are transferred to and from neurons, astrocytes, and microglia, which spread α-syn pathology in the olfactory bulb and the gut and then throughout the Parkinson’s disease (PD) brain and exacerbate neurodegenerative processes.

exosomes extracellular vesicles Parkinson’s disease pathogenesis therapeutics α-synuclein

1. Role of Exosomes in the Pathogenesis of Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world after Alzheimer’s disease, affecting 1–2% of the population over the age of 65 ^[1]. There are approximately seven million PD cases in the world; approximately one million of those cases are in the United States ^[2]. As the population ages, the burden on society attributable to PD is expected to increase substantially. The main pathological changes in PD are a progressive loss of dopamine (DA)-secreting neurons in the substantia nigra, a significant decrease of DA in the striatum, and the appearance of eosinophilic inclusions in the cytoplasm of DA neurons in the substantia nigra, namely Lewy bodies (LBs) ^[3]. The progressive loss of nigrostriatal neurons leads to the appearance of classical parkinsonian motor symptoms (e.g., bradykinesia, tremor, and rigidity) and numerous non-motor symptoms (e.g., depression, constipation, pain, gastrointestinal dysfunction, and sleep problems) ^[4]^[5]. The presence of α-synuclein (α-syn) aggregates in LBs ^[3], approximately 90% of which are phosphorylated on serine residue 129 ^[6], and the finding that mutations in the α-syn gene, SNCA, cause familial PD ^[7]^[8]^[9]^[10] and accelerate the pathogenic aggregation of α-syn ^[11]^[12], strongly suggested a role for α-syn in the pathogenesis of PD.

Prions are infectious agents in which the conformationally altered protein, PrP^Sc, recruits and corrupts its counterpart protein, PrP^C, generating self-propagating, misfolded species that spread from cell to cell ^[13]. According to the prion hypothesis of PD ^[14], like prion proteins, misfolded α-syn is transmitted from diseased cells to healthy cells, thereby spreading α-syn pathology in the PD brain ^[15]^[16]. The notion that EXs can be used as a carrier of toxic, misfolded proteins, such as α-syn, is an important tenet of the prion hypothesis of PD and is well supported by evidence. In vitro experiments provided the first evidence that newly synthesized monomeric and aggregated α-syn was released into the extracellular environment ^[17]^[18]^[19], a finding consistent with the presence of α-syn in human cerebrospinal fluid and blood plasma in both PD and normal human subjects ^[20]^[21]. Interestingly, EXs provide an environment conducive to α-syn aggregation ^[22]. In vitro studies have demonstrated α-syn release in EXs from donor neurons, uptake by recipient neurons, and subsequent cell death of recipient neurons ^[23]^[24]^[25]. When EXs harvested from the brain tissue of dementia with Lewy bodies patients were injected into the brains of mice, α-syn was taken up by neurons and astrocytes, and intracellular α-syn accumulation was observed ^[26]. Additional support for the prion hypothesis of PD comes from a study that examined the EXs isolated from the serum of PD patients, which contained a higher content of α-syn phosphorylated at serine residue 129 and oligomeric and monomeric α-syn than controls. In vitro studies demonstrated that the PD EXs, which contained an abundant amount of toxic, misfolded α-syn, were taken up by recipient cells, and acted as a seed or template to induce the aggregation of endogenous α-syn in recipient neurons. Interestingly, in human midbrain DA neuron cell cultures, pathogenic, misfolded α-syn was secreted in EXs via an autophagic secretory pathway ^[27]. Moreover, PD EX administration to mice resulted in DA neuron degeneration, microglial cell activation, and motor deficits ^[28]. Notably, neuron-to-neuron, neuron-to-microglia, microglia-to-neuron, neuron-to-astrocyte, and astrocyte-to-neuron transfer of α-syn has been demonstrated (Figure 1) ^[29]^[30]^[31]^[32]^[33].

Figure 1. The transfer of α-syn to and from neurons, astrocytes, and microglia. The transfer of α-syn to astrocytes and microglia results in their activation. Activated astrocytes and microglia release ROS, pro-inflammatory cytokines and chemokines, which contribute to the neurodegenerative processes in PD. The figure was created with BioRender.com https://app.biorender.com/ (accessed on 24 March 2023).

2. Pathogenic α-Syn-Containing Exosomes as Therapeutic Targets

Given the abundance of evidence implicating α-syn-containing EXs in the pathogenesis of PD, a logical therapeutic approach for PD is to minimize or eliminate the pathogenic effects of α-syn-containing EXs. This could be accomplished by decreasing EX biogenesis in parent cells, removing pathogenic EXs from circulation, and inhibiting EX uptake by the recipient cells (Figure 2A–D).

Figure 2. Approaches to minimize or eliminate the pathogenic effects of α-syn-containing EXs in PD. (A). The major steps in the biogenesis of α-syn-containing EXs. Therapeutic approaches may target key proteins involved in each of these steps. (B). An EX that contains pathogenic, misfolded α-syn and expresses the tetraspanins, CD9 and CD63, is sequestered by antibodies directed against CD9 and CD63 and then cleared from circulation. (C). α-Syn-containing EXs are taken up by recipient cells by clathrin-mediated endocytosis. Therapeutic approaches may target proteins involved in EX uptake. Note that there are numerous ways that EXs can be taken up by recipient cells including caveolin-mediated endocytosis, lipid raft-mediated endocytosis, micropinocytosis, phagocytosis, and membrane fusion ^[34]. (D). There are numerous ways to load therapeutic cargos into EXs and deliver them to target cells in the brain, as described in the text. The figure was created with BioRender.com https://app.biorender.com/ (accessed on 24 March 2023).

2.1. Decreasing Exosome Biogenesis

Several proteins responsible for EX biogenesis have been identified as targets to decrease pathogenic EX formation. EXs are formed by the invagination of the MVB system and their fusion with the plasma membrane ^[35]. As EX formation requires either endosomal sorting complexes required for transport (EXCRT)-dependent or ESCRT-independent cargo sorting at the MVB and MVB-plasma membrane fusion, related proteins can be regarded as potential therapeutic targets (Figure 2A) ^[36]. Two extensively studied proteins are the ALG-2-interacting protein X (ALIX) and the Rab protein ^[37]^[38]^[39]. During EX biogenesis, ALIX proteins are associated with the invagination of the MVB membrane by recruiting ESCRT proteins. Treatment with ALIX small interfering RNA (siRNA) and siRNA directed against the ALIX ligand, syntenin, suppressed ALIX function, resulting in reduced EX biogenesis ^[37]. Rab27a and Rab27b are notable as they are involved in the process of MVB fusion with the plasma membrane ^[35]^[40]. Knockdown or silencing of Rab27a and Rab27b reduced the number of EXs released ^[41]. In addition, the inhibition of two Rab27 effectors, Slp4 and Slac2b, also reduced the number of EXs released ^[40]. GW4869 is a potent neutral sphingomyelinase inhibitor that blocks EX production by preventing the formation of intraluminal vesicles (ILVs) (Figure 2A) ^[42]. Pretreatment of α-syn-activated microglia with GW4869 decreased the release of cathepsin L-containing EXs from microglia, which prevented neuronal death ^[43]. Similarly, treatment with GW4869 decreased EX release by activated microglia and prevented the death of DA neurons in midbrain slice cultures ^[44]. Systemic administration of DDL-112, an inhibitor of neutral sphingomyelinase, decreased EX biogenesis, reduced the number of α-syn aggregates in the substantia nigra, and improved motor function in an α-syn mouse model of PD ^[45].

2.2. Depleting Circulating Pathogenic Exosomes

After EXs are released from parent cells, they are either taken up by neighboring cells or travel to distant recipient cells to deliver their cargo. One interesting strategy to deplete pathogenic EXs from circulation is to use EX-specific antibodies so that EXs can be removed by the immune system (Figure 2B). The administration of anti-CD9 and anti-CD63 antibodies resulted in phagocytosis of the antibody-bound EXs by macrophages (Figure 2B) ^[46].

2.3. Inhibiting Exosome Uptake by Recipient Cells

In an attempt to ameliorate EX-mediated pathogenic cell-to-cell communication, researchers have inhibited EX uptake by recipient cells (Figure 2C) ^[47]^[48]. Endocytosis inhibitors have been heavily studied as potential therapeutics, as EXs are primarily taken up by recipient cells via endocytosis ^[34]. Cytochalasin D inhibits phagocytosis and endocytosis by blocking actin polymerization and inducing depolymerization of actin filaments ^[47]. Cancer-associated fibroblast-derived EXs were not effectively taken up by cancer cells in the presence of cytochalasin D ^[47]. Dynasore blocked the uptake of cancer cell-derived EXs due to an endocytosis-inhibiting effect ^[48]. In addition, the destabilization of lipid rafts in the plasma membrane is another strategy for inhibiting EX uptake (Figure 2C) ^[49]^[50].

3. Exosomesas Therapeutic Delivery Systems in Parkinson’s Disease

The first-line treatment for PD is the administration of DA and/or by administering agents that increase DA in the brain, specifically, the striatum. Although DA-replacement therapy benefits many PD patients, its therapeutic window is limited due to its decreasing efficacy and increasing side effects, such as dyskinesias ^[51]^[52]. Importantly, delivering DA to the brain or agents that increase DA in the brain is difficult due to the blood–brain barrier (BBB). For example, although L-3,4-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for PD symptoms, approximately 1% of the L-DOPA administered systemically reaches the brain ^[53]. After L-DOPA has reached the brain, it must be converted to DA by DOPA decarboxylase, which is less active in the brains of patients with PD ^[54]. Moreover, long-term administration of L-DOPA is marred by the emergence of abnormal involuntary movements called L-DOPA-induced dyskinesias ^[53].

EXs have the potential to serve as carriers of therapeutic agents into the diseased PD brain, in part, due to their ability to readily cross the BBB ^[55]^[56], the potential for targeted delivery of exosomal cargo over long distances, and immune resistance ^[57]. The intravenous administration of DA-encapsulated blood EXs readily crossed the BBB and delivered DA to the brain, including the striatum and substantia nigra. DA-encapsulated EXs increased brain DA content by greater than fifteen-fold and resulted in motor behavioral improvements and increases in DA synthetic enzymes and enzymes against oxidative stress in a 6-hydroxydopamine (6-OHDA) model of PD. Importantly, compared to the intravenous administration of free DA, DA-encapsulated EXs had greater therapeutic efficacy and lower toxicity ^[58]. Intranasal administration of catalase-loaded EXs was neuroprotective in a 6-OHDA model of PD ^[59]. The administration of MSC-derived EXs rescued DA neurons in a 6-OHDA model of PD ^[60]. Stem cell-derived EXs carry beneficial microRNAs (miRNAs) that reduce neuroinflammation in animal models of PD. For example, miR-133b, one of the miRNAs downregulated in PD, can promote neurite outgrowth in both in vitro and in vivo models of PD ^[61]. In addition, EXs isolated from human neural stem cells (NSCs) exerted a protective effect on PD pathology in a 6-OHDA in vitro and an in vivo mouse model of PD by reducing intracellular ROS and counteracting the activation of apoptotic pathways. NSC-derived EXs carry anti-inflammatory factors and specific miRNAs (i.e., has-miR-182-5p, has-miR-183-5p, has-miR-9, and has-let-7) involved in cell differentiation that contributed to decreased cell loss ^[62].

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