LPAR3: a shared target for neurodegenerative diseases?

Neurodegenerative diseases are often studied in isolation due to the vast differences in their underlying causes, the diversity in neuron types affected, and the variations in their clinical symptoms. However, there are common elements among these diseases, namely neuroinflammation, mitochondrial pathology, and an association with the gut–brain–immune axis that together suggest that these diseases are more similar to each other than they first seem (Zhang et al., 2023). Despite this, efforts have generally focused on developing therapies aimed at the source of the diseases while less focus has been on developing therapies that might impact a mutual downstream pathway. Reasons for this may include (1) the bias that each disease is unique and must be approached by targeting the initiating cause(s), (2) our lack of understanding of how all the common elements fit together among these diseases, and (3) the uncertainty that a shared element might be a successful target. Indeed, if it is challenging to target even one individual cause of one neurodegenerative disease, how could we expect to target a member of a downstream pathway for an effective treatment of multiple diseases? The discovery of an orally delivered bacteria that is broadly efficacious in neurodegenerative disease models through the production of an agonist of the lysophosphatidic acid receptor 3 (LPAR3), a G-protein coupled receptor involved in mitochondrial health, has presented a door to new possibilities (Acton et al., 2024).

LPAR3 (also known as LPA3, LPA₃, or EDG7) is one of several receptors that bind endogenously produced lysophosphatidic acids (LPAs). LPAs are a group of signaling lipids, each of which has a glycerol 3-phosphate head group and a fatty acid chain. Several naturally occurring LPAs differ in their chain length and saturation with the most common forms in human serum identified as 16:0, 16:1, 18:0, 18:1, 18:2, and 20:4. LPAR3 has a higher affinity for LPAs with unsaturated than saturated fatty acid chains with a rank order of potency of 18:3 = 18:2 > 18:1 = 20:4 >> 16:0 = 18:0 (Fujiwara et al., 2005). While LPAR3 has a high affinity for these LPAs, a complete analysis of other possible phospholipid agonists has not yet been performed. Farnesyl phosphate and farnesyl pyrophosphate have been reported to be antagonists and elevated levels of farnesyl pyrophosphate have been found in male Alzheimer’s disease (AD) patients (Liliom et al., 2006; Eckert et al., 2009). The synthetic compound Ki16425 is frequently used in vivo for blocking the activity of LPAR3 as well as another LPAR, LPAR1. In addition to LPAR3 and LPAR1, there are now at least four other major receptors (LPAR2, LPAR4, LPAR5, and LPAR6) that have been shown to signal in response to LPAs. LPAR1, LPAR2, and LPAR3 are within the EDG family of G-protein coupled receptors, which also comprises the sphingosine-1-phosphate receptors, targets of several drugs for multiple sclerosis (MS) and ulcerative colitis. Of the LPARs, LPAR1 has been the most studied, and antagonists to LPAR1 are currently in clinical trials for fibrotic diseases and MS. For some time, LPAs and their receptors have been known to modify cellular functions such as cytoskeletal reorganization, cell proliferation, migration, and cell survival. They also impact larger-scale functions including inflammation, myelination, nervous system development, response to injuries, central nervous system (CNS) angiogenesis, neuropathic pain, and more. LPARs are likely to have different roles in these processes given differences in their tissue distribution and differences in their activated downstream pathways; indeed, there is evidence that they may work in opposition to one another in the control of some processes (Geraldo et al., 2021). To our knowledge, however, LPAR3 is the only LPA receptor that has been associated with mitochondrial health (Chiang et al., 2022).

Importance of mitochondrial quality control in keeping neuroinflammation at bay: Mitochondrial dysfunction is one of the common elements in neurodegenerative diseases such as Parkinson’s disease (PD), Huntington’s disease (HD), AD, amyotrophic lateral sclerosis (ALS), and Friedreich’s Ataxia. Since mitochondria are the main generators of energy-containing adenosine triphosphate (ATP) molecules, this organelle’s health is critical to cells, particularly those cells requiring high levels of energy. During the production of ATP, the oxidative phosphorylation pathway (OXPHOS) forms small amounts of deleterious reactive oxygen species (ROS) as byproducts which can severely damage proteins and lipids. Therefore, a well-orchestrated system of antioxidants, such as reduced glutathione, and antioxidant enzymes such as glutathione peroxidase 1 and superoxide dismutase type 1 and type 2 (SOD1 and SOD2), exists so that cells can keep ROS below a tipping point to avoid toxicity and ultimately cell death. This control, particularly important in the case of neurons, keeps the cells healthy and the immune system quiescent (Figure 1).

Figure 1.

LPAR3 attenuation of damage amplification.

Neurons are maintained in a healthy state in a quiescent immune environment through mitochondrial quality control and the support of glial cells. When injury to the mitochondria occurs or when pathogens or debris are encountered, glial cells such as microglia may become activated, and astrocytes may become reactive to address the damage. If the damage becomes amplified, by repeated insult or due to an inability to turn off inflammation, neurons will ultimately degenerate. LPAR3 agonism appears to prevent the worsening of the outcomes regardless of the source of the damage. Created with BioRender.com. cGAS-STING: Cyclic GMP-AMP synthase stimulator of interferon genes; NLRP3: nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3; ROS: reactive oxygen species.

If mitochondrial pathology occurs, neurons can become vulnerable to future impairment or death. In addition to damage by its own generation of ROS, mitochondrial dysfunction can occur through many mechanisms such as mutations, damage by toxins, aging, or by a reduction in oxygen availability. Examples of mitochondrial-associated proteins with identified mutations that can lead to disease include PTEN-induced kinase 1, frataxin, and TAR DNA-binding protein 43, which can result in PD, Friedreich’s Ataxia, and ALS, respectively. Types of toxins that impact mitochondria and can lead to neurodegeneration include inhibitors of OXPHOS (chemotherapies such as cisplatin and pesticides such as rotenone) and heavy metals. Toxins have been associated with chemo-induced peripheral neuropathy, PD, AD, ALS, and autism spectrum disorder among others. Aging also affects mitochondria through the accumulation of mutations and oxidative damage and contributes to many neurodegenerative diseases. Indeed, mitochondrial health plays a role either directly, or indirectly, in most neurodegenerative diseases. This may be because, in addition to its production of ROS, mitochondria can become severely damaged and release its double-stranded DNA into the cytosol or extracellular space which triggers a local immune response. This involves recognition by the cGAS-STING (cyclic GMP-AMP synthase stimulator of interferon genes) pathway and amplification of the NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome pathway which together boost inflammation. These proinflammatory pathways, which also involve the participation of glial cells, play a role in the degradation of neurons.

Role of glial cells in neuronal support and neuroinflammation: Microglia and astrocytes are two of the main neuronal support cells in the CNS, which assist in keeping the neurons healthy and functioning properly. The microglia, macrophage-like cells in the CNS, surveil the area for invaders and perform cleanup of debris such as fragmented mitochondria. Like other immune cells, however, microglia can have both anti-inflammatory and proinflammatory effects depending on their phenotype and the environment. If they are unable to quickly clear pathological stimulators, such as amyloid-β and tau proteins in AD or α-synuclein in PD, they can become part of a chronic inflammatory process. Astrocytes, as another major support cell, normally sustain the function of the blood–brain barrier and assist neurons through many biochemical and physical interactions. These cells, especially when they become reactive, can release neurotrophic factors, chemokines, and cytokines, and the impact can be either neuroprotective or neurotoxic. The immune response within this support system is designed to turn on when needed and off when not needed to keep the neurons healthy and functioning properly. However, when quality control measures are insufficient or damage is not addressed efficiently, the result may be greater inflammation with the recruitment of additional immune cells, sometimes including those from the periphery. Uncontrolled chronic inflammation ultimately leads to neurodegeneration. Thus, it is important that the organism has a mechanism by which to push the balance from an inflammatory state back to a quiescent state for neuronal recovery. From recent data, it appears that LPAR3 may be part of that important off switch for inflammation.

Role of lysophosphatidic acid receptor 3 in neuroinflammation: In the brain, LPA receptors have been identified in both neurons and glial cells, and in some cases, their expression depends on the presence of inflammatory stimuli. LPAR3 is expressed in normal human astrocytes, and in mice LPAR3 is upregulated in neurons after injury and upregulated acutely but not chronically by the introduction of inflammatory bacterial lipopolysaccharide in the brain (Goldshmit et al., 2010; Plastira et al., 2020). Recent data suggests that LPA receptors may work as a complex system to control inflammatory responses, and results of studies in mouse MS models support the hypothesis that LPAR1 and LPAR3 may work in opposition to one another in the modulation of inflammation (Acton et al., 2024; Poon et al., 2024). One hypothesis is that LPAR1, which signals at low LPA levels, is proinflammatory while LPAR3, which requires higher levels of LPA for signaling, is anti-inflammatory. If correct, activation of LPAR1 may be part of the ‘on switch’ and activation of LPAR3 may be part of the ‘off switch’ for CNS inflammation.

LPAR3 was first identified as a possible ameliorator of neuroinflammation in mouse models of PD, MS, and HD using a dual LPAR1/LPAR3 inhibitor, Ki16425. In the MS model, no exogenous agonist was used, and in the PD and HD models gintonin, an extract of ginseng containing LPAs, was the source of the agonist (Choi et al., 2018, 2021; Jang et al., 2019). The recent discovery that a selective potent agonist of LPAR3 was produced by Bacillus velezensis ADS024, a bacterium with gastrointestinal anti-inflammatory activity (Irwin et al., 2024), gave us the opportunity to test its impact on animal models of PD, MS, and HD and to further expand our knowledge of LPAR3 agonism to other neurodegenerative diseases. Both mutations and toxins were tested as initiators of pathology in these models. We observed improved outcomes in eight models of five neurodegenerative diseases which included three mouse models (PD, MS, and chemo-induced peripheral neuropathy) and five zebrafish models (two in PD, MS, ALS, and HD) indicating that the pathway is present and a target for neuroinflammatory pathology in both fish and mammals. The data also demonstrated that Ki16425 largely attenuated the improvements at concentrations that did not affect endogenous activity suggesting that LPAR3 agonism is responsible for disease modulation (Acton et al., 2024). Based on these findings, it is now evident that (1) agonism of LPAR3 improves outcomes in many neuroinflammatory disease models and efficacy is independent of the initiating cause, (2) the outcomes improved are diverse and include motor movement, pain sensation, and behavior indicating an effect on multiple neuron types, and (3) delivery of a select bacteria to the gastrointestinal tract can positively impact diseases in the CNS. How, though, does an LPAR3 agonist like the one in ADS024 have such a broad effect? The answer may lie in its ability to protect the mitochondria.

Lysophosphatidic acid receptor 3 in the mitochondrial quality control pathway: Recent data suggests that LPAR3 plays a role in the maintenance of proper mitochondrial function and the protection of cells against oxidative damage (Figure 2). In their effort to understand premature aging in Hutchinson-Gilford progeria syndrome, the Lee laboratory demonstrated that LPAR3 is important for mitochondrial homeostasis against oxidative stress (Chiang et al., 2022). LPAR3 was found to be important for mitochondrial ADP-ATP exchange, maintenance of mitochondrial membrane potential, and curtailing ROS accumulation in cells. LPAR3 also attenuated the cisplatin-induced release of cytochrome C which can lead to mitochondrial-induced apoptosis. Our data is consistent with this since cisplatin-induced peripheral neuropathy as well as apoptosis was attenuated by ADS024 (Acton et al., 2024; Irwin et al., 2024). Furthermore, Chiang et al. (2022) demonstrated that agonism of LPAR3 strongly induced ROS-eliminating proteins Nrf2, glutathione peroxidase 1, NQO1, and SOD2 and ameliorated oxidative stress induced by H₂O₂ treatment. LPAR3 has also been shown to play a role in protection from ferroptosis, a process in which lipid peroxides accumulate leading to programmed cell death (Huang et al., 2024). The complete LPAR3 pathway that leads to multiple protective effects on mitochondria is just beginning to be defined and future research is warranted. Thus far, the demonstration of LPAR3-induced mitochondrial protection provides a viable mechanism as to how LPAR3 agonism can be effective in models of so many neurodegenerative diseases.

Figure 2.

Role of LPAR3 in the maintenance of mitochondrial health and protection against oxidative damage.

Mitochondrial-related functions are reported to be increased (green arrows and boxes) and decreased (red blocking lines and boxes) by LPAR3 agonism. LPAR3 increases the protein level of the transcription factor Nrf2 which is upstream of ROS-eliminating proteins such as Gpx1, NQO1, and SOD2. LPAR3 increases mitochondrial membrane potential (OXPHOS pathway) and increases mitochondrial ADP-ATP exchange through an increase in ANT2 expression. The impact of a potential increase in calcium trafficking through VDAC1 association with IP3R1 is not yet clear since changes in mitochondrial calcium trafficking can have either positive or negative effects on metabolism and energy production. Pathways reduced by LPAR3 include lipid oxidation, iron accumulation and ferroptosis, ROS accumulation, and cytochrome C-induced apoptosis. Organelles are not at scale. Created with BioRender.com. ANT2: Adenine nucleotide translocase 2; Ca²⁺: calcium; Cyt C: cytochrome C; ER: endoplasmic reticulum; Fe: iron; Gpx1: glutathione peroxidase 1; IP3R1: inositol 1,4,5-trisphosphate receptor type 1; Keap1: kelch-like ECH-associated protein 1; LPAR3: lysophosphatidic acid receptor 3; Nrf2: nuclear factor erythroid 2-related factor 2; -OH: oxidized; OXPHOS: oxidative phosphorylation; PM: plasma membrane; ROS: reactive oxygen species; VDAC1: voltage-dependent anion-selective channel 1.

Conclusion: For years, neurodegenerative diseases have been treated as unique, however, the evidence that they have much in common is growing. We now have sufficient data from animal models to provide evidence that a shared therapeutic target may indeed exist. This G-protein coupled receptor target, LPAR3, appears to be positioned at the intersection of mitochondrial pathology, neuroinflammation, and the gut–brain–immune axis. Until now, LPAR3 has not received great attention, but with the identification of an LPAR3 agonist-producing bacteria that can improve outcomes in models of multiple neurodegenerative diseases, the hope is that additional effort will be put towards a more detailed understanding of the exact role of LPAR3 in neuronal protection. ADS024 has been shown to be safe and well-tolerated in a 28-day human clinical trial (NCT04891965), therefore not only does the ADS024 bacterium give hope to the possibility of a new treatment, but its production of an LPAR3 agonist provides a solid mechanistic argument as to how a bacterial species can impact neurodegenerative diseases through the gut–brain–immune axis. The next step is to determine whether an orally available LPAR3 agonist, like that which is present in ADS024, has the same efficacy against neurodegenerative diseases in humans as it does in fish and mice.

Both authors work on behalf of Adiso Therapeutics and have stock options. No conflicts of interest exist between Adiso Therapeutics and publication of this paper.