<EM>MITF</EM> MUTANT MICE ARE A NOVEL MULTISYSTEM MODEL OF PARKINSON’S DISEASE

Parkinson’s disease (PD) is most well known as a movement disorder, but peripheral symptoms are increasingly important and are present in advance of diagnostic motor signs. LRRK2 (Leucine-Rich Repeat Kinase 2) mutations are a major contributor to genetic risk for PD. LRRK2 regulates lysosomes, and members of the MIT-TFE transcription factor family, including TFEB, TFE3, and MITF, act downstream of LRRK2 to control lysosomal gene expression. Although TFEB is neuroprotective when overexpressed in animal models of PD, the role of MITF remains unexplored. This study provides the first systematic behavioural and neuropathological assessment of Mitf mutant mice as a novel model for both central and peripheral aspects of PD. Male mice aged 3, 6, and 12 months were studied (N= 6-16; wild-type; Mitf ^{mi-enu22(398)}/Mitf ^{mi-enu22(398)} and Mitf ^Mi-wh/+). Motor performance, grip strength, and gait were assessed alongside gastrointestinal transit time and cold sensitivity. Total brain volume, striatal tyrosine hydroxylase immunofluorescence, and astroglial activation were quantified. Both Mitf mutant lines displayed heightened cold sensitivity and delayed gastrointestinal transit already at 3 months, resembling early non-motor features of PD. Striatal tyrosine hydroxylase was reduced by 3 months, and importantly, whole-brain volume was reduced at 12m. Marked astrocytosis in the hippocampus and substantia nigra was detected at 12 months of age. Taken together, the sensory and autonomic behavioural impairments and the neuropathological changes closely parallel key features of PD. These findings support Mitf mutant mice as valuable models of the multisystem nature of PD.