Malassezia and Parkinson's Disease

Abstract

Parkinson's disease (PD) is a common debilitating neurodegenerative disease caused by a loss of dopamine neurons in the substantia nigra within the central nervous system (CNS). The process leading to this neuronal loss is poorly understood. Seborrheic dermatitis (SD) is a common benign inflammatory condition of the skin which mainly affects lipid-rich regions of the head and trunk. SD is caused by over proliferation of the lipophilic fungus Malassezia. PD and SD are strongly associated. The increased PD risk following an SD diagnosis (OR = 1.69, 95% CI 1.36, 2.1; p < 0.001) reported by Tanner and colleagues remains unexplained. Malassezia were historically considered commensals confined to the skin. However, many recent studies report finding Malassezia in internal organs, including the CNS. This raises the possibility that Malassezia might be directly contributing to PD. Several lines of evidence support this hypothesis. AIDS is causally associated with both parkinsonism and SD, suggesting that weak T cell-mediated control of commensal microbes such as Malassezia might contribute to both. Genetic polymorphisms associated with PD (LRRK2, GBA, PINK1, SPG11, SNCA) increase availability of lipids within human cells, providing a suitable environment for Malassezia. Four LRRK2 polymorphisms which increase PD risk also increase Crohn's disease risk; Crohn's disease is strongly associated with an immune response against fungi, particularly Malassezia. Finally, Malassezia hypha formation and melanin synthesis are stimulated by L-DOPA, which could promote Malassezia invasiveness of dopamine neurons, and contribute to the accumulation of melanin in these neurons. Although Malassezia's presence in the substantia nigra remains to be confirmed, if Malassezia play a role in PD etiology, antifungal drugs should be tested as a possible therapeutic intervention.

Keywords: Malassezia; Parkinson's disease; immunodeficiency; immunosenescence; seborrheic dermatitis.

Figure 1

Model of CD4+ T cell immunosenescence, which illustrates how CD4+ T sensitivity to different microbes can change. Each column represents a sub-population of naïve CD4+ T cells which has an identical T cell receptor (TCR). Some TCRs are cognate with Malassezia peptides (green), others with Candida peptides (orange) or Treponema peptides (blue). Recognized peptides will vary between individuals based on their MHC Class II alleles. This model can explain early onset seborrheic dermatitis, parkinsonism and neurosyphilis in AIDS patients, as the concentration of all TCRs decline. It can also explain why seborrheic dermatitis and Parkinson's disease are so strongly associated in immunocompetent individuals: the concentrations of TCRs cognate with Malassezia peptides decline, allowing Malassezia to over proliferate due to a weak CD4+ T cell-mediated immune response. This has been measured in seborrheic dermatitis (70), but not in Parkinson's disease. These data were manually generated for illustrative purposes only (they are not measurements from patients).

Figure 2

These plots illustrate how the green region of Figure 1 is expected to vary with age (mainly due to thymic involution and immunosenescence). In the top plot, the seborrheic dermatitis (SD) threshold is reached first, which means SD will precede Parkinson's disease (PD). In the bottom plot, the PD threshold is reached first, which means PD will precede SD. These thresholds are likely influenced by genes controlling the strength of Th1 immunity against Malassezia. The PD threshold could also be affected by lipid levels (modulated by GBA, LRRK2, PINK1, SPG11) and lipid droplet accessibility by lipases (modulated by SNCA). The low rate of SD diagnosis preceding a PD diagnosis [4%] reported by Tanner and colleagues (46) suggests that PD and SD share few genetic/environmental risk factors, and that the PD threshold is usually crossed first in individuals who develop PD.