LRP10 as a novel α-synuclein regulator in Lewy body diseases

Autosomal dominant variants in LRP10 have been identified in patients with Lewy body diseases (LBDs), including Parkinsons disease (PD), Parkinsons disease-dementia (PDD), and dementia with Lewy bodies (DLB). Nevertheless, there is little mechanistic insight into the role of LRP10 in disease pathogenesis. In the brains of non-demented individuals, LRP10 is typically expressed in non-neuronal cells like astrocytes and neurovasculature, but in idiopathic and genetic cases of PD, PDD, and DLB it is also present in -synuclein-positive neuronal Lewy bodies. These observations raise the questions of what leads to the accumulation of LRP10 in Lewy bodies and whether a possible interaction between LRP10 and -synuclein plays a role in disease pathogenesis. Here, we demonstrate that wild-type LRP10 is secreted via extracellular vesicles (EVs) and can be internalised via clathrin-dependent endocytosis. Additionally, we show that LRP10 secretion is highly sensitive to autophagy inhibition, which induces the formation of atypical LRP10 vesicular structures in neurons in human induced pluripotent stem cells (iPSC)-derived midbrain-like organoids (hMLOs). Furthermore, we show that LRP10 overexpression leads to a strong induction of monomeric -synuclein secretion, together with time-dependent, stress-sensitive changes in intracellular -synuclein levels. Interestingly, patient-derived astrocytes carrying the c.1424+5G>A LRP10 variant secrete aberrant high-molecular-weight species of LRP10 in EV-free media fractions. Finally, we show that the truncated LRP10splice protein binds to wild-type LRP10, reduces LRP10 wild-type levels, and antagonises the regulatory effect of LRP10 on -synuclein levels and distribution. Together, this work provides initial evidence for a functional role of LRP10 in LBDs by regulating intra- and extracellular -synuclein levels, and pathogenic mechanisms linked to the disease-associated c.1424+5G>A LRP10 variant, pointing towards potentially important disease mechanisms in LBDs.