Dopaminergic neurons display antigens: autoimmunity in Parkinson’s disease pathology
Parkinson’s disease (PD) is a chronic, progressive degenerative disorder of central nervous system. Its pathology is characterised by selective loss of dopaminergic neurons in the nigrostrial pathway, and clinical manifestations are exhibited as motor impairments, including resting tremor, bradykinesia, and rigidity. Current medications offer symptomatic relief but, to date, do not address the dopaminergic neuronal death. The lack of understanding of the etiology of this selective cell death still remains the major stumbling block in the development of neuroprotective therapies. Current research implicates a number of key molecular mechanisms compromising the function and survival of this specific subset of neurons, and these involve abnormal protein accumulation and phosphorylation, mitochondrial dysfunction, oxidative damage and deregulated kinase signalling. Although the current hypothesis focuses on the toxic aftermath of α-synuclein protein deposits, an alternative theory pioneered by Dr. Sulzer’s group within the Department of Neuorology at Columbia University, implies a role of the immune system in PD pathology, more specifically suggesting that Parkinson’s is in fact an autoimmune disease.
As mentioned, pathological features of PD include the loss of nigrostriatal dopamine neurons and the formation of Lewy bodies rich in fibrillar α-synuclein. This 140-amino-acid protein is abundantly expressed at a relatively high level throughout the brain (Iwai et al., 1995) and is thought to play physiological roles in the regulation of the dopamine transporter (Sidhu et al., 2004). However, misfolding of α-synuclein into protofibrils and higher-order oligomers (Uversky et al., 2002) leads to a toxin gain of function (Martin et al., 2006), which is associated with the pathogenesis of neurodegeneration (Giasson et al., 2000). Furthermore, this protein has been genetically linked to the early onset of familial PD (Kruger et al., 1998). However, the mechanism by which α-synuclein causes neurodegeneration remains unclear.
In addition to α-synuclein dysfunction, PD pathology is also characterised by a sustained microglial reaction throughout the disease progression Imamura et al., 2003). Microglial cells are the resident immune cells in brain and play a major part in the neuroinflammatory response (Soulet and Rivest, 2008). On an epidemiological level, the contribution of an inflammatory response in neurodegeneration is evidenced by the decreased risk of falls in PD patients on administering the non-steroidal anti-inflammatory drug (NSAID), ibuprofen (Gagne and Power, 2010). On a cellular and molecular level, the significant elevation in inflammatory cytokines has been found in both the cerebrospinal fluid and postmortem brain of PD patients (Mogi et al., 1994). These cytokines have been reported to induce the death of dopaminergic cells (Vivekanantham et al., 2015), and thus facilitating neurodegeneration in PD.
Dr. Sulzer’s group have recently identified the presence of antigens displayed on dopaminergic neurons in post-mortem brain tissues. It has long been argued that brain cells are safe from immune cell attack because they do not display these molecular markers for immune cell target recognition. However, these new findings indicate that they can in fact be targeted. Abnormal processing of self-proteins can produce epitopes, which are presented by major histocompatibility complex (MHC) proteins to be recognised by specific T cells that have escaped tolerance during thymic selection (Marrack and Kappler, 2012). Such actions by the acquired immune system have been implicated in autoimmune disorders, including type-1 diabetes. Although PD has not before been linked to autoimmunity, it does demonstrate altered protein processing. As previously described, activation of microglia and elevated cytokine levels have described in PD patients, indicating a role of the innate immune system. But what evidence is there to implicate the acquired immune system?
Rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD was initially provided by Brochard, et al (2009). It was found that CD8+ and CD4+ T cells, but importantly not B cells, infiltrate the substantia nigra (SN) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration, which is consistent with postmortem human PD specimens. Further investigation concluded that T cell-mediated dopaminergic toxicity is almost exclusively arbitrated by CD4+ T cells (Brochard et al., 2009). The Sulzer group from Columbia University, more recently, reported antigen presentation by MHC class I expression in dopamine neurons in the SN of adult human PD brains (Sulzer et al., 2017). This was the result of activation by cytokines released from microglia. CD8+ T cells kill neurons that present the appropriate combination of MHC class I and peptide (Cebrián et al., 2014). On comparison of PD patients to age-match healthy controls, the group then identified two antigenic regions in α-synuclien (Fig. 1a). The first near the N terminus elicited an apparent class II restricted IL-5 and IFNγ response (Fig. 1b–d). The second antigenic region was near the C terminus required phosphorylation of amino acid residue S129 that resulted in a markedly higher IL-5 responses in patients with Parkinson’s disease than in healthy controls. The Y39 antigenic region is noticeably close to the α-synuclien mutations that cause Parkinson’s disease (A30P, E46K, H50Q, G51D, A53T; Hernandez et al., 2016), and phosphorylated S129 residues, found in the second antigenic region, are present at high levels in Lewy bodies of patients with Parkinson’s disease (Fujiwara et al., 2002). Finally, blood tests have revealed that people with Parkinson’s show an immune response to these antigens, while people who don’t have the condition do not (Sulzer et al., 2017).
Figure 1│α-synuclein autoimmune responses are directed against two regions. a, Sequence of α-synuclein. Antigenic regions are highlight with dashed line with amino acids Y39 and S129 shown in bold. b-d, Magnitude of responses expressed as SFC per 106 PBMC’s per peptide and participant combination. Left, response to all overlapping native α-synuclein 15-mer peptides in patients with PD (n=733) and control (n=372). Right, response against specific 15-mers. Grey shading indication the antigenic region containing Y39. e-g, Magnitude of responses. Left, response to all native phosphorylated S129 α-synuclein 15-mer peptides in patients with PD (n=150) and control (n=72). Right, response against specific S129 peptides. Closed circles, patients with PD (n=19, † indicates peptides; n=25, all other peptides); open circles, control (n=12). Two-tailed Mann-Whitney U-test; NS, not significant.
These findings are the first time the immune system has been associated with a major pathological role in Parkinson’s. They present an argument for the classification of PD as an autoimmune disorder. However, what isn’t clear is which comes first: does the immune response directly causes neuron death, or does the disease result in a heightened immune response? If suppression of this autoimmune response does indeed stop disease progression, these findings could provide an attractive target for therapeutic intervention.
Blog written by Victoria Miller
Brochard et al., J. Clin. Invest. (2009) 119, 182–192.
Cebrián et al., Nat. Commun. (2014) 5, 3633.
Fujiwara et al., Nat. Cell Biol. (2002) 4, 160–164.
Gagne & Power, Neurology (2010), 74, 995–1002.
Giasson et al., Science (2000), 290, 985–989.
Hernandez et al., J. Neurochem. (2016) 139, 59–74.
Imamura et al., Acta Neuropathol. (2003), 106, 518–526.
Iwai et al., Neuron (1995), 14, 467–475.
Kruger et al., Nat. Genet.(1998), 18, 106–108.
Marrack & Kappler, Cold Spring Harb. Perspect. Med. (2012) 2, a007765.
Martin et al., J. Neurosci. (2006), 26, 41–50.
Mogi et al., Neurosci. Lett. (1994), 165, 208–210.
Sidhu et al., FEBS Lett. (2004), 565, 1–5.
Soulet & Rivest, Curr. Biol. (2008), 18, R506–508.
Sulzer, Nature (2017) 0.
Uversky et al., J. Biol. Chem. (2002), 277, 11970–11978.
Vivekanantham et al., Int. J. Neurosci. (2015), 125, 717–725.