Gaucher disease (GD), a prevalent lysosomal storage disorder, offers a compelling case study for investigating the role of the complement system in disease progression and tissue inflammation. This rare genetic condition arises from mutations in the GBA1 gene, leading to defects in the enzyme acid β-glucosidase (GCase). As a result, β-glucosylceramide (GC or GL1) accumulates within immune cells, contributing to chronic tissue inflammation and organ failure. My kaboratory aims to unravel how complement system activation exacerbates these inflammatory processes and to identify potential therapeutic targets.

The complement system, a crucial component of the innate immune response, operates through three primary pathways: classical, alternative, and lectin. These pathways converge on key components such as C3 and C5, which play pivotal roles in immune response and inflammation. Complement activation leads to the production of various mediators, including C3a and C5a. C3a interacts with C3aR receptors, while C5a binds to C5aR1 and C5aR2 receptors, influencing immune cell recruitment and activation. C5a stands out due to its potent role as a chemoattractant and activator of innate and adaptive immune responses, including the production of cytokines and enzymes essential for cellular function.

In Gaucher disease, the accumulation of GC disrupts normal complement regulation, leading to chronic inflammation and tissue damage. My research has uncovered a critical link between C5a and its receptor C5aR1 in this context. Using a combination of Gba1 mutant mice, chemically induced Gaucher-like mice, and human samples, we have demonstrated that the C5a-C5aR1 axis significantly contributes to the inflammatory processes of the disease (Figure.1). This connection, detailed in our study published in Nature (Pandey et al., 2017), features the importance of complement-mediated immune responses in Gaucher disease pathology. By bridging the gap between complement system dysfunction and Gaucher disease pathology, our work not only enhances our understanding of this rare disorder but also opens up exciting possibilities for targeted interventions.

Our current research focuses on the C5a-C5aR1 axis as a promising target for new treatments in Gaucher disease and potentially other lysosomal storage and neurodegenerative disorders. We are actively exploring how blocking this axis through genetic or pharmacological means can reduce brain inflammation and stop or lessen disease symptoms. This work aims to reveal whether targeting the C5-C5a-C5aR1 interaction can mitigate disease impacts and pave the way for innovative therapies across various lysosomal storage diseases.

References

1. Pandey MK, Burrow TA, Rani R, Martin LJ, Witte D, Setchell KD, McKay MA, Magnusen AF, Zhang W, Liou B, Köhl J, and Grabowski GA. Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease. Nature. 2017;543:108-112.
2. Pandey MK, Grabowski GA, Köhl J. An unexpected player in Gaucher disease: The multiple roles of complement in disease development. Semin Immunol. 2018;S1044-5323 (17) 30104-5.
3. Trivedi VS, Magnusen AF, Rani R, Marsili L, Slavotinek AM, Prows DR, Hopkin RJ, McKay MA, Pandey MK. Targeting the Complement–Sphingolipid System in COVID-19 and Gaucher Diseases: Evidence for a New Treatment Strategy. Int. J. Mol. Sci. 2022;23:14340.
4. Pandey MK. Exploring Pro-Inflammatory Immunological Mediators: Unraveling the Mechanisms of Neuroinflammation in Lysosomal Storage Diseases. Biomedicines. 2023;11(4):1067.
5. Pandey MK. Uncovering the Lipid Web: Discovering the Multifaceted Roles of Lipids in Human Diseases and Therapeutic Opportunities. Int J Mol Sci. 2023 Aug 25;24(17):13223.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and associated with significant neuroinflammation. Recent research has illustrated the critical role of complement activation components in PD, providing new avenues for diagnosis and treatment. Our studies focus on understanding how abnormalities in complement activation contribute to the disease and exploring potential therapeutic strategies.

Complement system dysregulation is known to impact various brain diseases, including ischemia, intracerebral hemorrhage, traumatic brain injury, systemic lupus erythematosus, amyotrophic lateral sclerosis, neuromyelitis optica spectrum, Alzheimer’s, and Huntington’s diseases. In the context of Parkinson's disease, abnormal activation of complement components such as C3, C3b/iC3b, CR3, C5, C5a, and the terminal complement complex (MAC/C5b-9) has been linked to disruptions in the blood-brain barrier, increased neuroinflammation, and neuronal damage. Elevated levels of these components have been observed in the substantia nigra, neuronal cells, and cerebrospinal fluid (CSF) in both mouse and human models of PD.

Our research influences insights from Gaucher disease to address the elevated risk of developing PD linked to the accumulation of GC and its impact on development of abnormal α-synuclein species. Our studies suggest that GC - α-synuclein species-mediated complement activation is a critical driver in this process. We hypothesize that in PD, the buildup of GC and/or - α-synuclein species drives  activation of the complement cascades,  particularly C3 and its derivatives (C3b/iC3b) initiates a force of events that results in the overproduction of C5 convertases. This, in turn, leads to the generation of C5a and the formation of the membrane attack complex (MAC). These complement-mediated changes are thought to drive intense neuroinflammation and contribute to the death of dopaminergic neurons, accelerating disease progression and severity. Our findings suggest that the C3-C3b-iC3b-CR3 network facilitates the release of C5 convertases, promoting the transformation of C5 into C5a and C5b. C5a binds to the C5aR1 receptor on microglial cells, driving their activation, leading to the massive production of pro-inflammatory cytokines and subsequent neuronal loss. Concurrently, the formation of MAC/C5b-9 directly induces neuronal death (Figure 2).

We are currently investigating the specific roles of C3a and C5a in microglial and neuronal cell activation, pro-inflammatory cytokine production, and dopaminergic neuron loss in Parkinson’s disease models. Additionally, we are exploring whether genetic or pharmacological targeting of the C3a-C3aR and C5a-C5aR1 axes can reduce brain inflammation and neurodegeneration in PD mouse models.

Our goal is to refine diagnostic approaches by identifying complement activation components as biomarkers for Parkinson’s disease. Furthermore, we aim to develop novel therapeutic strategies targeting complement pathways to mitigate neuroinflammation and slow disease progression.

References

1. Magnusen AF, Hatton SL, Rani R, Pandey MK. Genetic Defects and Pro-inflammatory Cytokines in Parkinson's disease. Front Neurol. 2021;12:636139.
2. Hatton SL, Pandey MK. Fat and Protein Combat Triggers Immunological Weapons of Innate and Adaptive Immune Systems to Launch Neuroinflammation in Parkinson disease. Int. J. Mol. Sci. 2022;23:1089.
3. Pandey MK. The Role of Alpha-Synuclein Autoantibodies in the Induction of Brain Inflammation and Neurodegeneration in Aged Humans. Front. Aging Neurosci. 2022;14:90219.

The laboratory has made several discoveries pertaining to the identification of mechanisms that cause immune inflammation in Gaucher disease. These include the identification of glucosylceramide (GC) loaded DCs and CD4+T cells, which upon stimulation showed increased production of pro-inflammatory cytokines, C-C, and C-X-C chemokines. These data suggested that DCs and CD4+T cells interaction drive inflammatory responses that lead to Gaucher disease manifestation. We now seek to determine if other APCs such as Mɸs, PMNs, and B cells also interact with certain T cells to trigger innate and adaptive immune responses. The lab is extensively involved in defining the signaling cascades that trigger GC induced immune inflammation in Gaucher disease.

Another focus in the Pandey lab is to determine the role of pro-inflammatory cytokines in facilitating immune cell attack to the brain in Gaucher type-II and -III, and, Parkinson diseases. Using mouse models of neurodegenerative diseases, Dr. Pandey’s lab is currently characterizing residential and CNS-infiltrating immune cells and their effector function for persuading neuronal loss and behavioral deficits.