SPG11
Spatacsin (Colorectal carcinoma-associated protein) (Spastic paraplegia 11 protein) [KIAA1840]
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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 [i]Malassezia[/i]. PD and SD are strongly associated. The increased PD risk following an SD diagnosis (OR = 1.69, 95% CI 1.36, 2.1; [i]p[/i] < 0.001) reported by Tanner and colleagues remains unexplained. [i]Malassezia[/i] were historically considered commensals confined to the skin. However, many recent studies report finding [i]Malassezia[/i] in internal organs, including the CNS. This raises the possibility that [i]Malassezia[/i] 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 [i]Malassezia[/i] might contribute to both. Genetic polymorphisms associated with PD ([i]LRRK2, GBA, PINK1, SPG11, SNCA[/i]) increase availability of lipids within human cells, providing a suitable environment for [i]Malassezia[/i]. Four [i]LRRK2[/i] polymorphisms which increase PD risk also increase Crohn's disease risk; Crohn's disease is strongly associated with an immune response against fungi, particularly [i]Malassezia[/i]. Finally, [i]Malassezia[/i] hypha formation and melanin synthesis are stimulated by L-DOPA, which could promote [i]Malassezia[/i] invasiveness of dopamine neurons, and contribute to the accumulation of melanin in these neurons. Although [i]Malassezia[/i]'s presence in the substantia nigra remains to be confirmed, if [i]Malassezia[/i] 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