For Seminar Meeting on 2021.04.06
Abstract:
Lysosomes have fundamental physiological roles and have previously been implicated in
Parkinson’s disease1–5. However, how extracellular growth factors communicate with
intracellular organelles to control lysosomal function is not well understood. Here we report
a lysosomal K+channel complex that is activated by growth factors and gated by protein
kinase B (AKT) that we term lysoKGF. LysoKGFconsists of a pore-forming protein TMEM175 and
AKT: TMEM175 is opened by conformational changes in, but not the catalytic activity of, AKT.
The minor allele at rs34311866, a common variant inTMEM175, is associated with an increased
risk of developing Parkinson’s disease and reduces channel currents. Reduction in lysoKGF
function predisposes neurons to stress-induced damage and accelerates the accumulation
of pathological α-synuclein. By contrast, the minor allele at rs3488217—another common
variant ofTMEM175, which is associated with a decreased risk of developing Parkinson’s
disease—produces a gain-of-function in lysoKGFduring cell starvation, and enables neuronal
resistance to damage. Deficiency in TMEM175 leads to a loss of dopaminergic neurons and
impairment in motor function in mice, and aTMEM175loss-of-function variant is nominally
associated with accelerated rates of cognitive and motor decline in humans with Parkinson’s
disease. Together, our studies uncover a pathway by which extracellular growth factors
regulate intracellular organelle function, and establish a targetable mechanism by which
common variants ofTMEM175confer risk for Parkinson’s disease.