Table 4. Effects of gene expression strategies and pharmacological compounds in experimental in vivo models of Parkinson’s disease.

In regards to experimental design, preclinical studies can be sorted in four groups depending on the lag time between the induction of the pathology and the administration of the neuroprotective compound. The therapeutic compound can be administered: (I) prophylactically, (II) concomitantly or (III) after onset of symptoms. The fourth group (IV) is based on the use of transgenic animals. In most cases, the therapeutic compound is administered to adult transgenic animals, although rare examples of delivery after onset of symptoms exist (Anle138b for instance). AAV, adeno-associated virus; CMA, chaperone-mediated autophagy; TFEB, transcription factor EB; LAMP2a, lysosome-associated membrane protein 2 type a; α-syn, α-synuclein; mTOR, mammalian target of rapamycin; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PLK2, polo-like kinase 2; PP2A, Protein phosphatase-2A ; Thy1, THYmocyte differentiation antigen 1 ; Hsp70, heat shock protein 70; Hsp104, heat shock protein 104; LV, lentivirus ; Snca, synuclein gene nomenclature ; PDGFβ, platelet-derived growth factor-β; Pffs: α-syn preformed fibrils.

Target	Mechanism of action	Animal Model	Main outcome	Experimental design	References
Autophagic gene expression
TFEB	Enhancement of lysosomal biogenesis	Rat AAV2/6 - α-syn	Neuroprotection Decreases α-syn pathology	II	123
LAMP2a	Boosting of CMA function	Rat AAV2/6 - α-syn	Neuroprotection Decreases α-syn pathology	II	124
Beclin 1	Enhancement of autophagy	Mice PDGFß- α-syn	Decreases α-syn pathology	IV	122
		Rat AAV2/6 - α-syn	Neuroprotection Decrease α-syn pathology	II	123
Autophagy-enhancing drug
Rapamycin	Inhibition of mTOR	Mice - MPTP	Neuroprotection	I	87
Temsirolimus	Rapamycin analog	Rat AAV2/6 - α-syn	Neuroprotection Decreases α-syn pathology	III	123
Trehalose	Enhancement of autophagy	Mice Parkin deleted / tau overexpressing	Neuroprotection	IV	127
Modulation of protein phosphorylation
PLK2	Phosphorylation of α- syn at S129	Rat AAV2/6 - α-syn	Neuroprotection Decreases α-syn pathology	II	134
PP2A (Pharmacological activation)	Dephosphorylation of α- syn at S129	Mice Thy1- α-syn	Restores motor behaviour Decreases α-syn pathology and glial activation	IV	136
Inhibition of α-syn truncation
Calpastatin (Overexpression of inhibitor)	Truncation inhibitor	Mice Thy1-A30P- α-syn	Decreases α-syn pathology and glial activation	IV	138
Disaggregation of α-syn
Hsp70 (Overexpression)	Molecular chaperone	Fly- α-syn	Neuroprotection	IV	139
Hsp70 (Pharmacological activation)	Molecular chaperone	Fly - α-syn	Neuroprotection	IV	141
HSP104	Molecular chaperone	Rat LV-A30P - α-syn	Neuroprotection Decreases α-syn pathology	II	63
Anle138b	Oligomer modulator	Mice Rotenone Thy1 - A30P - α-syn	Decreases behavioral impairments Decreases α-syn pathology Increases in disease-free survival	IV - III	144 & 148
CRL01	Molecular tweezer	Zebrafish - α-syn	Increases survival Decreases α-syn pathology	IV	145
KYP-2047	Prolyl oligopeptidase inhibitor	Mice Thy1-A30P - α-syn Sncatm(A30P)	Fiber protection Decreases α-syn pathology	IV	146 & 147
α-syn antibodies
9E4	Passive immunization	Mice PDGFß - α-syn	Decreases α-syn pathology	IV	149
AFFITOPE® technology	Active immunization	Mice Thy1 - α-syn PDGFß - α-syn	Improves behavioral impairments Decreases α-syn pathology and glial activation Induce inflammatory response	IV	150
Syn303	Passive immunization	Mice Pffs induced degeneration	Reduces motor dysfunction Decreases dopaminergic cell loss and α-syn pathology	II - III	157