Prodromal neuroinvasion of pathological α-synuclein in brainstem reticular nuclei and white matter lesions in a model of α-synucleinopathy

Neuropathological observations in neurodegenerative synucleinopathies, including Parkinson disease, implicate a pathological role of alpha-synuclein accumulation in extranigral sites during the prodromal phase of the disease. In a transgenic mouse model of peripheral-to-central neuroinvasion and propagation of alpha-synuclein pathology (via hindlimb intramuscular inoculation with exogenous fibrillar alpha-synuclein: the M83 line, expressing the mutant human Ala53Thr alpha-synuclein), we studied the development and early-stage progression of alpha-synuclein pathology in the CNS of non-symptomatic (i.e. freely mobile) mice. By immunohistochemical analyses of phosphroylated alpha-synuclein on serine residue 129 (p-S129), our data indicate that the incipient stage of pathological alpha-synuclein propagation could be categorized in distinct phases: (i) initiation phase, whereby alpha-synuclein fibrillar inoculum induced pathological lesions in pools of premotor and motor neurons of the lumbar spinal cord, as early as 14 days post-inoculation; (ii) early central phase, whereby incipient alpha-synuclein pathology was predominantly detected in the reticular nuclei of the brainstem; and (iii) late central phase, characterized by additional sites of lesions in the brain including vestibular nuclei, deep cerebellar nuclei and primary motor cortex, with coincidental emergence of a sensorimotor deficit (mild degree of hindlimb clasping). Intriguingly, we also detected progressive alpha-synuclein pathology in premotor and motor neurons in the thoracic spinal cord, which does not directly innervate the hindlimb, as well as in the oligodendroglia within the white matter tracts of the CNS during this prodromal phase. Collectively, our data provide crucial insights into the spatiotemporal propagation of alpha-synuclein pathology in the nervous system of this rodent model of alpha-synucleinopathy following origin in periphery, and present a neuropathological context for the progression from pre-symptomatic stage to an early deficit in sensorimotor coordination. These findings also hint towards a therapeutic window for targeting the early stages of alpha-synuclein pathology progression in this model, and potentially facilitate the discovery of mechanisms relevant to alpha-synuclein proteinopathies. In a rodent model of synucleinopathy, Ferreira et al., delineate the spatiotemporal progression of incipient alpha-synuclein pathology (of peripheral origin) in the CNS. The authors show early affection of brainstem reticular nuclei in non-paralyzed mice, and pathological white matter lesions in relation to the neuronal pathology.

Automated summary

The study in a rodent model demonstrates that peripheral inoculation of alpha-synuclein can lead to pathological progression in the central nervous system, with initial lesions appearing in motor neurons and the spinal cord. These findings provide valuable insights into the propagation of alpha-synuclein pathology in the nervous system.