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Table 1 Reported effects of autophagy-enhancing agents in preclinical PD models

From: Therapeutic potential of autophagy-enhancing agents in Parkinson’s disease

  Target Agent Main effect PD model Ref
mTOR-dependent pathways AMPK Metformin Reduced cell death Drosophila melanogaster mutated for LRRK2 [95]
MPTP mice [96]
Reduced phospho-Ser129 α-syn levels α-Syn overexpressing SH-SY5Y cells [98]
AMPK AICAR Reduced cell death LRRK2-mutated Drosophila Melanogaster [95]
AMPK (SIRT1) Resveratrol Increased α-syn clearance α-Syn overexpressing PC12 cells [100]
Reduced cell death Rotenone-exposed SH-SY5Y cells [100, 101]
Improved mitochondrial functioning Cultured PARK2-mutant fibroblasts [102]
Beclin-1 PREP inhibitor (KYP-2047) Decreased oligomeric α-syn, increased striatal DA levels A30P α-syn transgenic mice [140]
Beclin-1 Isorhynchophylline Increased α-syn clearance N2a cells transfected for WT, A53T, and A30P α-Syn; Embryonic DA neurons [141]
   Increased α-syn clearance/Reduced α-syn accumulation WT, A30P, and A53T α-syn expressing PC12 cells [4]
B103 neuronal cells expressing α-syn and Beclin-1 [103]
α-Syn-transgenic mice [68]
α-Syn-transgenic rats [70]
mTORC1 Rapamycin and Rp analogues (CCI-779, RAD001 and AP23573) Reduced phospho-Ser129 α-syn levels α-Syn overexpressing SH-SY5Y cells [98]
Reduced cell death Rotenone-exposed SH-SY5Y cells [82, 92, 93]
6-OHDA and MPP+ treated PC12 cells [83]
MPTP mice [50, 83]
α-Syn-transgenic mice [68]
α-Syn-transgenic rats [70]
Drosophila melanogaster mutated for PINK-1 and Parkin [87]
Improved motor function, reduced synaptic injury A53T- α-Syn transgenic mice [84]
Reduced levodopa-induced dyskinesia 6-OHDA mice; 6-OHDA rats [85, 86]
Reduced mitochondrial dysfunction Rotenone-exposed SH-SY5Y cells [82, 92]
Drosophila melanogaster mutated for PINK-1 and Parkin [87]
TFEB 2-HPβCD Increased α-syn clearance H4 human neuroglioma cells transfected for α-syn [143]
mTor-independent pathways IMPase Lithium Increased clearance of A53T and A30P α-syn PC12 cells expressing A53T and A30P α-syn [88]
Reduced apoptosis and mitochondrial dysfunction Rotenone-exposed SH-SY5Y cells [92, 93]
Improved motor function, increased viability DA cells in the SN, decreased loss of DOPAC MPTP mice (combined treatment with lithium and sodium valproate) [94]
Ins Sodium Valproate Reduced apoptosis and mitochondrial dysfunction Rotenone-exposed SH-SY5Y cells [92]
Improved motor function, increased viability DA cells in the SN, decreased loss of DOPAC MPTP mice (combined treatment with lithium and sodium valproate) [94]
Ins Carbamazepine Reduced apoptosis and mitochondrial dysfunction Rotenone-exposed SH-SY5Y cells [92]
SLC2A transporters Trehalose Reduced cell loss Rotenone-treated rats and PC12 cells [107]
MPTP mice; A53T α-Syn overexpressing rats [108, 109]
Increased α-syn clearance PC12 cells overexpressing WT and A53T α-Syn [104, 106]
NB69 human neuroblastoma cells [105]
Rotenone-treated PC12 cells [107]
A53T α-Syn overexpressing rats [109]
Increased clearance of detergent-insoluble α-syn A53T α-Syn overexpressing mice [110]
Reduced motor deficits MPTP mice; A53T α-Syn overexpressing rats [108, 109]
Reduced neuroinflammation MPTP mice [108]
Unknown SMERs (SMER 10, 18 & 28) Increased A53T α-syn clearance PC12 cells expressing A53T α-syn [112]
Unknown Latrepirdine Increased α-syn clearance Saccharomyces cerevisiael, SH-SY5Y cells expressing α-syn and WT mice [115]
Decreased cell death Saccharomyces cerevisiae expressing α-syn [115]
Unknown Spermidine Reduced motor dysfunction, increased lifespan; Reduced neuronal cell loss Drosophila melanogaster expressing α-syn; Caenorhabditis elegans expressing α-syn [118]
Unknown (polyphenols) Curcumin Reduced α-syn accumulation SH-SY5Y Cells expressing WT and A53T α-syn [119]
Kaempferol Reduced ROS, apoptosis, and mitochondrial dysfunction Rotenone-exposed SH-SY5Y cells, mouse primary neuronal culture [120]
C. album polyphenol fractions Reduced α-syn accumulation; reduced ROS Hu neuroglioma H4 cells expressing αSyn; Yeast cells expressing αSyn [121]
Unknown Nilotinib Increased α-syn clearance; improved motor function Mice expressing A53T α-synuclein; mouse primary cortical neurons [122, 123]
Reduced cell death Mice expressing A53T α-synuclein [122]
Lysosomes GCase Ambroxol Restoration of lysosomal function; increased GCase activity GBA1 mutant fibroblasts [150, 151]
Reduction of oxidative stress GBA1 mutant fibroblasts [150]
GCase Isofagomine Improved motor performance, increased α-syn clearance, reduced neuroinflammation WT-α-syn overexpressing mice [159]
  Lysosome Acidic Nanoparticles Restoration of lysosomal function; reduced DA cell loss Cultured ATP13A2 and GBA-mutant fibroblasts; MPTP mice [145]
  1. Abbreviations: Ref reference number, 2-HPβCD 2-Hydroxypropyl-β-cyclodextrin, α-syn α-synuclein, DA dopaminergic, DOPAC 3,4-Dihydroxyphenylacetic acid, ROS reactive oxidative stress, WT wild-type, 6-OHDA 6-hydroxydopamine, MPTP 1-methyl-4-fenyl-1,2,3,6-tetrahydropyridine, UPS ubiquitin-proteasomal system