Table 1.

Summary of PD animal models.

Model	Characteristics	Most Common Induction Protocols and Time Perspective (Acute/Chronic)	Main Known Affected Mechanisms	Behavioural/ Symptomatic Changes	When to Use this Model
6-OHDA	Highly oxidisable DA analogue enters the cell through DAT, which allows selective damage to catecholaminergic neurons by cytotoxicity.	Single stereotaxic administration – % of neuronal death is dose-dependent MFB, SN or striatum (Bilateral or unilateral) Characteristics: MFB and SN - rapid, generalised degeneration of the damaged nucleus Striatum - progressive loss of dopaminergic neurons of the SNpc Reserpine, an inhibitor of VMAT, can also be injected to protect noradrenergic terminals from 6-OHDA toxicity.	1) intra- or extracellular auto-oxidation of 6-OHDA, which favours the production of hydrogen peroxide, superoxide and hydroxyl radicals; 2) formation of hydrogen peroxide due to the action of monoamine oxidase, and 3) direct inhibition of mitochondrial respiratory chain complex I and IV. Oxidative stress, neurodegeneration, neuroinflammation, and neuronal death by apoptosis. Does not promote α-syn accumulation.	Bradykinesia, cognitive deficits, Enteric Nervous System (ENS) dysfunctions, changes in circadian timing (day/night activity), depressive-like behaviour, changes in gait parameters [112], and nociceptive threshold [22, 113, 114] Unilateral induction Forepaw asymmetry use (cylinder test) [23], Rotational motor behaviour (apomorphine [93] or amphetamine tests) (Postural asymmetry).	Evaluate the molecular basis of cytotoxicity and cell processes activated by oxidative stress (local neuroinflammation and DA/catecholaminergic neuron death). Trialling of symptomatic therapies Studies of levodopa-induced dyskinesia and other side effects of dopaminergic drugs Studies of motor and non-motor symptoms.
MPTP	Crosses the BBB. In the brain, astrocytes convert MPTP to a toxic metabolite (MPP+) by the enzyme monoamine oxidase-B.	s.c., i.p, i.m., i.v. i.n. and brain injection (SN) Acute - single injection (more common for brain injection) Chronic - multiple injections % of neuronal death is dose/ frequency dependent Characteristics: damage to the nigrostriatal pathway, loss of striatal GABAergic neurons and neurons in the VTA and retrorubral nucleus, as well as reactive gliosis.	ATP deprivation, inhibition of mitochondrial complex I and IV, and consequently oxidative stress, activation of the mitochondrial apoptotic cascade, excitotoxicity, inflammation (microglial activation), dysregulation of the UPS, and the formation of inclusion bodies α-syn (mRNA increase and aggregation in the brain) [86] and tau accumulation [89].	Reduced locomotion and rearing (open field) – rodent models - Primate models have similarities to human symptoms.	Induction of bilateral dopaminergic cell loss Closer to human parkinsonism symptoms, including dyskinesia after levodopa therapy (mainly in primates) Testing of potential symptomatic therapies and stem cell therapies.
Rotenone	Crosses the BBB. Isolated from tropical plants, acts as a herbicide and insecticide.	s.c., i.p., and brain injection (SN or striatum – less common) 1.0-2.5 mg/kg Chronic – multiple injections % of neuronal death is dose/ frequency-dependent.	Mitochondrial dysfunction (mitochondrial complex-I inhibitor), oxidative stress. Alteration in lipid and glutathione metabolism (complex I inhibition) α-syn increase, presence of Lewy body-like inclusions TH-positive neuron decrease.	Increased number of falls on the rotarod, increased immobility and decreased climbing on forced swimming test.	Induction of bilateral dopaminergic cell loss. Non-selective for dopaminergic system. Trialling of symptomatic therapies.
Lipopolysaccharide (LPS)	Crosses the BBB. An endotoxin from the outer membrane of bacteria is known as a potent trigger of inflammation.	i.p., i.v. (0.02 mg/kg to 3 mg/kg) or brain injection (2 mg - 10 mg). Acute - single injection Chronic - multiple injections Characteristics: Astrocyte and microglia activation, as well as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokine expression.	A robust activation of microglia and astrocytes; release of neurotoxic factors.	Increased number of falls on the rotarod.	Investigation of general neuroinflammatory processes. Induction of bilateral dopaminergic cell loss. Non-selective for the dopaminergic system. Useful in trialling novel PET ligands of neuroinflammation.
Proteasome inhibition	Inhibitors of proteasome activity.	Stereotaxic striato-nigral or i.c.v injections of lactacystin.	Inhibition of proteasome, which leads to α-syn aggregation and DA neuron loss. I.c.v. model also targets noradrenaline and serotonin neurotransmission and leads to neuroinflammation.	Motor dysfunction on catalepsy test, cylinder test and rotational behaviour.	Study deficiencies in proteasome activity, study dopaminergic as well as non-dopaminergic aspects, as well as motor and non-motor symptoms.
Genetic models	Focus on genes with mutations observed in familial PD. Most common target genes: PARK1, LRRK2, PINK1, PARKIN, DJ-1 (PARK7), GBA.	Models based on overexpression or depletion of genes.	Altered mitophagy, dysfunction of the ubiquitin-proteasome pathway, fragmented mitochondria and altered ROS, promoting DA neuron loss.	Increased number of falls on rotarod and decreased overall motor activity in beam walk test [115].	Investigate genes and mutations related to PD development.
Recombinant adeno-associated viral vectors (AAV)	Focus on targeting the SN and promoting an overexpression of α-syn.	Local stereotaxic injection of rAAV in the nigral system and the disease severity can be controlled by adjustment of α-syn dose/expression.	Aggregation of phosphorylated α-syn in terminals, which leads to progressive dopaminergic neuron loss.	Impairment of motor function in the cylinder test, the rotarod test and the open field test.	Useful to understand α-syn toxicity but not prion-like behaviour.
Preformed fibrils (PFF)	Focus on targeting the dopaminergic system and promoting PFF spreading.	Stereotaxic injection of α-syn PFFs or brain lysate/ homogenate from PD patients in the dopaminergic system PFF needs to be properly sonicated to an average of 50nm or smaller before brain injection.	Development of Lewy body-like inclusions promoting DA neuron loss. Misfolded α-syn spreads gradually after injection into areas anatomically connected to striatum and becomes bilaterally located with time. α-syn fibrils promote progressive pathological synaptic impairment prior to neurodegeneration, accompanied by neuroinflammation.	No clear changes in motor behaviour have been reported. Due to the slow development of this model, motor impairments may only become apparent at later timepoints, or with higher amounts of administered PFFs.	Study prion-like behaviour of α-syn propagation Studies of prodromal PD, disease progression, and longitudinal changes Trialling of neuroprotective therapies Useful in trialling novel α-syn PET ligands.