Contrasting Behavioural and Biochemical Characteristics of Normal and Spontaneously α‐Synuclein‐Deficient Mice Treated With <scp>MPTP</scp>

α-Synuclein is the primary toxic constituent of Lewy bodies, but its exact function under homeostatic conditions remains elusive. To better understand the role of α-synuclein, we compared two C57BL sub-strains: the normal α-synuclein-expressing J6 and the α-synuclein-deficient J6-OlaHSD, for behavioural, dopaminergic and glial integrity in substantia nigra (SN) and caudate putamen (CPu) before and after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. After MPTP treatment, J6 mice showed significant weight loss (-7% by Day 10), whereas OlaHSD mice maintained stable body weight. At baseline, J6 mice exhibited 33% higher locomotor activity but 38% more thigmotaxis, and 33% less endurance on the Rotarod test than OlaHSD mice. Loss of tyrosine hydroxylase-positive neurons was similar in OlaHSD (-40%) and J6 mice (-34%). J6 mice had double the SN GFAP-ir cells of J6-OlaHSD, a difference that was unchanged by MPTP treatment. In the CPu, MPTP increased GFAP-ir cells in both strains, but Iba1-ir cells significantly increased only in MPTP-treated OlaHSD mice, compared to J6 strain. We further compared the biochemical signatures using Raman micro-spectroscopy. The Raman spectra of the freshly cut SN sections showed a greater shift in the α-helix to β-sheet protein conformation ratio in MPTP-induced J6 mice, likely due to the absence of the Snca1 gene in OlaHSD mice. These findings suggest that the absence of α-synuclein plays a subtle role in the behavioural and neurochemical differences but has no significant effect on dopaminergic neurotransmission. It is therefore concluded that the presence of α-synuclein is important for non-dopaminergic behaviours such as anxiety-like behaviours and regulation of body weight. Under toxic challenge, gliosis in the SN and CPu may be regulated by α-synuclein. This study also emphasises the utility of Raman spectroscopy as a potential tool for identifying subtle protein conformation differences in mice with and without Snca1.