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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