Table 3.

Therapeutic approaches targeting metabolism or mitochondrial quality control

Substance	Scientific basis	Results from preclinical studies	Results from clinical trials
Metabolic remodeling
Glucagon-like peptide (GLP-1) agonists, e.g. exenatide, liraglutide	– Antidiabetic therapy with GLP-1 agonists (e.g., exenatide, liraglutide) is associated with reduced risk for developing PD.	– Preclinical studies in toxin-induced rodent models of PD (MPTP, rotenone, and 6-OHDA) suggested a neuroprotective potential for GLP-1 agonist treatment [257]. – The mechanism of action is still unclear. Currently, modulation of neuroinflammatory pathways, reduction of ROS, normalization of cellular Ca2+ levels, restoring mitophagy and improving overall bioenergetic efficiency is suggested [258]. – However, conflicting results exist, indicating exenatide may worsen aSYN accumulation [259].	– In a placebo-controlled trial exenatide treatment over 48 weeks resulted in clinical improvement of motor symptoms [260]. – A phase III trial (Exenatide-PD3; NCT04232969) is currently investigating the effect of a two-year exenatide treatment on motor symptomatology in PD patients [261]. – In a small double-blind, placebo-controlled, trial 52 weeks of liraglutide treatment resulted in significant improvement of non-motor symptoms and activities of daily living, while severity of motor symptoms was unchanged [262].
Peroxisome proliferator- activated receptor- γ (PPARγ) agonists, e.g., pioglitazone	– Antidiabetic treatment with pioglitazone is associated with a reduced risk for developing PD [256].	– Pioglitazone showed neuroprotective potential in a transgenic mitochondrial complex IV deficient mouse line of PD. – It also attenuated MPTP-induced dopaminergic neurodegeneration in a rodent model of PD [263]. – Mechanism of neuroprotection is unclear. Modulation of different cellular pathways including reduced neuroinflammation, suppressed nitric oxide synthase activity, improved proteasomal clearance, and enhanced mitochondrial biogenesis have been suggested [264].	– A phase II clinical trial investigating pioglitazone treatment over 44 weeks revealed no modification of disease progression in early PD patients [265].
Enhancing mitochondrial quality control
mdivi-1	– Excessive Drp1-mediated mitochondrial fission has been identified as a pathomechanistic pathway in PD [266]. – mdivi-1 blocks Drp1.	– mdivi-1 reduced proteinase K resistant aggregates and mitochondrial ROS production as well as improved autophagy and ATP production in aSYN overexpressing or PFF exposed cells in vitro [267–269]. – mdivi-1 rescued the motor phenotype und exerted neuroprotective effects in A53T-aSYN overexpressing rats, the rotenone- or MPTP-induced rodent model of PD, [267, 269] as well as in the PINK-KO [270] mice.	– mdivi-1 has not been tested in clinical trials yet.
Miro-targeting	– Prolonged retention of the outer mitochondrial membrane protein Miro on mitochondria disturbs mitophagy and thereby contributes to PD pathology [271].	– Reduction of Miro rescued mitophagy in human fibroblast cultures of PD patients and Drosophila models of PD [272, 273].	– Miro reducers have not been tested in clinical trials.
Increasing PINK1/Parkin levels	– Deficits in PINK1 and/or Parkin signaling are known causes of genetic PD.	– Several preclinical studies indicated that increasing levels of PINK1 or Parkin can recue MPTP induced neurodegeneration [274–276] or ameliorate aSYN mediated toxicity [277, 278].	– Compounds increasing PINK1/Parkin are currently not tested in clinical trials.