Rescue of α-synuclein aggregation in Parkinson’s patient neurons by synergistic enhancement of ER proteostasis and protein trafficking

Interaction of Alpha Synuclein and Microtubule Organization Is Linked to Impaired Neuritic Integrity in Parkinson’s Patient-Derived Neuronal Cells

“…Although the aetiology of PD may be multifactorial, elevated aSyn levels are assumed to be an important risk factor for aSyn aggregation. This is particularly supported by genetic evidence that SNCA duplication or triplication alone is sufficient to cause PD [20,21]. Extending our previous studies on hiPSC-derived neurons (CPNs and mDANs from SNCA Dupl PD patients [9,13], we confirm increased aSyn protein levels in hiPSC-derived cells carrying SNCA Dupl .…”

“…Thus, our current data suggest a neuronal differentiation-dependent decrease in bTubIII protein levels, which are linked to SNCA Dupl mDANs. Interestingly, the downregulation of tubulin elements was not described in other aSyn overexpression cell models, for example, in hiPSC-neurons with SNCA triplication [21,26]. It should be noted that tubulins are involved in a dynamic balance between microtubule assembly and disassembly processes and that their solubility is closely correlated to assembly extent, as indicated in Figures 2 and 5.…”

Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies

“…Another effect of asyn aggregation is mediated through its actions at the endoplasmic reticulum (ER), which becomes fragmented in PD, impairing proteostasis and the activation of unfolded protein response (UPR), and retention of GCase within the ER ( 113 ). Interestingly, the asyn-induced deficit of ER proteostasis was rescued by inhibitors of the ryanodine receptors which modulate ER calcium influx, including with diltiazem, an FDA approved drug for hypertension and angina.…”

Contribution of Autophagy-Lysosomal Pathway in the Exosomal Secretion of Alpha-Synuclein and Its Impact in the Progression of Parkinson’s Disease

“…GCase is an N-glycosylated protein synthesized and transported in vesicles from the ER-to-Golgi apparatus, where it is correctly folded through a maturation process before reaching the lysosomes. α-syn aggregation generated by wild-type SNCA triplication in PD patients iPSC-derived dopaminergic neurons was reported to disrupt the ER-GA trafficking by inhibiting the SNARE protein ykt6 ( Cuddy et al, 2019 ), depleting lysosomes from acid hydrolases, and increasing the accumulation of insoluble immature GCase in ER ( Stojkovska et al, 2021 ). Interestingly, using a pharmacological enhancer of ER proteostasis plus a farnesyltransferase inhibitor (FTI), which restores ykt6 activity, was reestablished GCase maturation and lysosomal activity, becoming a promising therapeutic strategy for future studies in synucleinopathies ( Stojkovska et al, 2021 ).…”

“…Several pharmacological agents targeting ALP components, especially lysosomal function, are active research topics in preclinical and clinical phases to PD and other synucleinopathies. They include the previously mentioned FTI, which restores the SNARE ykt6 activity, reestablishing lysosomal hydrolases maturation, and finally, the lysosomal activity ( Stojkovska et al, 2021 ) pharmacological agonists of lysosomal Ca 2+ channel, TRPML1, which has been shown to restore lysosomal exocytosis, enhancing α-syn secretion and decreasing accumulation in ATP13A2 patient iPSC-derived neurons ( Tsunemi et al, 2019 ); or the ambroxol, a cough syrup approved by the FDA since 1971, which has been reported to reduce α-synuclein levels in vitro and in vivo ( Migdalska-Richards et al, 2016 ), and to increase GCase expression and activity ( Migdalska-Richards et al, 2017 ). Ambroxol was shown to restore lysosomal exocytosis ( Magalhaes et al, 2018 ) and promote ER folding.…”