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

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.