Objective: Parkinson’s disease (PD) mouse model using 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was explored for pathological mechanisms driving non-motor symptoms (NMS). Aim was to map the behavioural changes to molecular correlates in degeneration of nigrostriatal pathway during disease progression.

Background: PD, the second most prevalent neurodegenerative disorder, was primarily defined by motor symptoms. The nigrostriatal pathway, involving dopaminergic neurons in the substantia nigra pars compacta (SNpc) and their striatal projections, was central to its pathology. Progressive neurodegeneration and dopamine loss drove motor deficits like resting tremors. However, NMS such as anxiety, depression, and olfactory dysfunction emerged early but remained undetected due to a lack of definitive biomarkers, complicating early diagnosis and intervention.

Method: MPTP, metabolized into 1-Methyl-4-phenylpyridinium (MPP⁺), selectively targeted SNpc dopaminergic neurons. C57BL/6 mice (4–5 months old) received subcutaneous sub-chronic MPTP to model slow neurodegeneration. Behavioural tests assessed anxiety-like behaviour and motor coordination, while biochemical and molecular analyses (immunohistochemistry, immunoblotting) were conducted at designated time points. Statistical significance was determined using Student’s t-test.

Results: NMS emerged by day 15 post-MPTP administration, accompanied by tyrosine hydroxylase (TH) loss and mild dopamine transporter (DAT) fibre loss in the striatum, while the SNpc remained unaffected and motor deficits were absent. By day 30, motor symptoms appeared, with TH loss extending to both regions. By day 60, dopaminergic degeneration progressed, with pronounced DAT fibre loss in the striatum and SNpc. Alpha-synuclein and its phosphorylated form showed a rising trend at days 15 and 30, becoming significantly elevated by day 60, reflecting PD pathology.

Conclusion: This sub-chronic MPTP model successfully recapitulated early-stage PD, with NMS preceding motor deficits. Pathological analyses revealed key PD-like features, including SNpc neurodegeneration, striatal DAT loss, and increased synuclein.

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/establishing-a-timeline-of-non-motor-and-motor-symptoms-progression-in-parkinsons-disease-using-a-sub-chronic-mptp-mouse-model/