Many lipid metabolism alleles are risk factors of Parkinson’s disease (Xicoy 2019).
Individuals who inherit non-functional GBA variants from each parent develop Gaucher disease (a lipid storage disorder), while those who inherit one non-functional GBA variant are at high risk of Parkinson’s disease (Trinh 2013). The GBA protein catalyzes a key lipid metabolism step: when this step is not performed, lipids accumulate within human cells (Hruska 2008).
Functional LRRK2 kinase variants are major risk factors of Parkinson’s disease (Trinh 2013). LRRK2 phosphorylates Rab proteins, which are essential to maintain the right amount of lipids within cells (Thirstrup 2017). LRRK2 risk allele Y1699C has been shown to increase lipid droplet sizes by phosphorylating Rab8 (Yu 2018). Interestingly, four LRRK2 risk alleles have been associated with Crohn’s disease (Rivas 2018; Hui 2018). Crohn’s disease is caused by an excessive immune response against Malassezia in the gut (Limon 2019).
Many other genetic risk factors of Parkinson’s disease cause lipid accumulation within human cells, including PINK1 (Choi 2014), SPG11 (Branchu 2017), SREFBF1 (Do 2011), DGKQ (Pankratz 2009), ASAH1 (Robak 2017) and SMPD1 (Gan-Or 2013).
Finally, mutations in SNCA are also a major risk factor of Parkinson’s disease (Trinh 2013). SNCA encodes the alpha-synuclein protein, which is abundant in the brain and often forms Lewy bodies in aging individuals. SNCA protects lipid droplets from lipases by “wrapping” them in an alpha-synuclein sheath (Cole 2002). Mutations in SNCA make it much less effective at protecting lipid droplets from lipases (Cole 2002).
Malassezia are lipid dependent fungi: they require lipids provided by the host to grow (Celis 2017) and obtain them by secreting lipases, which cleave fatty acids from human lipid droplets. In children fed with Intralipid, acute Malassezia infections occur where excess lipids accumulate inside the body (Redline 1981; Redline 1985; Shek 1989).
A simple explanation for the genetic risk factors of Parkinson's disease is that excess lipid availability in the body promotes Malassezia’s growth in the brain, and this results in the death of dopaminergic neurons.
This post was mainly based on Laurence 2019.
Animated Parkinson’s video: https://youtu.be/NEusgOerL5U
