This manuscript presents a 6-OHDA lesion model in the sheep. Strengths of the study are its novelty and originality (it is the first report of a 6-OHDA model in the sheep), the nice Figures, and the well-described and advanced methods, which will become a key reference for other groups interested in setting up this model. The study, however, has technical limitations that should be discussed, in particular:
(i) the failure to pick up a PD-relevant phenotype that is directly caused by the lesion (could this have been picked up using tests additional to the open field tracking?);
(ii) the presentation of drug-induced behavioural phenotypes of difficult interpretation (do the reported drug effects indicate an antiparkinsonian response, a dyskinetic response, or a neuropsychiatric disturbance?)
(iii) the omission to count the number of dopamine neurons in the substantia nigra, which is standard to do when developing a parkinsonian animal model. In fact, in the absence of this information, it is difficult to compare this model with those available in other species.

Requested specific revision:

1- Abstract “New therapeutic agents developed for treating neurological disorders are often tested successfully on rodents, and yet 80–90% of these prove ineffective when transitioning to clinical application. Testing in an appropriate large-animal model should improve translational success ….” In the opening of the Abstract, this tout-court questioning of rodent models seems misplaced and unnecessarily contentious (also because there is no evidence that candidate drug treatments tested with success in NHP models of PD have translated better to the clinic). Claiming that 80–90% of treatments tested in rodents fail in translation does not make this study more interesting. A more circumstantiated sentence is therefore recommended. For example, several advantages of large animal models of PD are mentioned in the Introduction, and these could be summarised here.

1. Results “…displayed minor motor impairments such as rigidity” : rigidity is tested by examining the muscle resistance to passive flexion-extension of the limbs, which was not done here. So the word rigidity is to be removed.

2. Results “qualitative behaviours that were observed before and after 6-OHDA treatment…are summarised in Table 2”: Table 2 only shows behaviours “during DA agonist trial. Please expand this Table (or add another Table) to summarise the behaviours observed after the lesion. In the Methods section, please explain how often the qualitative observations had been made, how, and for how long observation periods.

3. Table 1: this Table reports the stereotaxic injection coordinates used in individual animals, it is very technical and it should be placed in the Supplemental file, along with a legend (explaining why 9 animals have 2 ML coordinates, whereas 4 animals have only 1).

4. Results on TH immunohistochemistry and Fig 5A: there seems to be a lot of background in this TH immunostaining. If possible, it would be good to give it another try (at least on the nigral sections) using steps that can increase the signal to noise ratio in immunohistochemistry.

5. Discussion: it is currently too long (5.5 pages), contains many repetitions (including repetition of concepts given in the Introduction), and delves into some details of scarce importance. A major revision of the Discussion is needed. During this revision, please take the opportunity to address the technical limitations of the study mentioned in the first paragraph of this review.

Minor points:
- “A total of 13 female Romdale sheep, ranging from 36- 48 months of age”: What is the life span of a sheep? It would be nice to add this information somewhere, as animals with a long life span could be particularly useful in research related to brain aging /age related diseases (such as PD).