gms | German Medical Science

Question: Parkinson’s disease and multiple system atrophy (MSA) are synucleinopathies that are defined by the accumulation of aggregated and hyperphosphorylated alpha-synuclein within cells of the central nervous system. Recent evidence suggests that prion-like propagation along connected neurons results in the spreading of pathological forms of alpha-synuclein in the nervous system. We investigated whether human wild-type alpha-synuclein supports prion-like propagation of pathological alpha-synuclein in vivo.

Methods: We intrastriatally injected groups of adult Tg(SNCA)1Nbm/J mice with brain extracts from two patients with MSA, from two aged control subjects without neurological disorder, or with saline. Tg(SNCA)1Nbm/J mice do not express mouse but low levels of human wild-type alpha-synuclein and do not naturally develop any pathology or neurodegenerative disease. Injected mice were sacrificed at 3, 6, and 9 months post injection and were analyzed immunohistochemically and biochemically for the presence of pathological alpha-synuclein.

Results: Mice injected with brain extracts from MSA or aged control subjects but not saline showed progressive accumulation of aggregated alpha-synuclein in neurons of the central nervous system. Aggregates of alpha-synuclein were hyperphosphorylated and co-stained for ubiquitin and p62 that target proteins for degradation. Pathological alpha-synuclein aggregates were first detectable in the ipsilateral brain hemisphere and over time in the contralateral hemisphere and in more rostral and caudal areas.

Conclusions: Our findings show that brain extracts from MSA patients but not saline induce pathological changes in the central nervous system of Tg(SNCA)1Nbm/J mice. Our data corroborate that pathological alpha-synuclein may spread prion-like along neuronal networks. Furthermore, we show that human wild-type alpha-synuclein supports propagation of pathological alpha-synuclein. Interestingly, brain extracts from aged control subjects without neurological disorder equally induced synucleinopathy in the brains of Tg(SNCA)1Nbm/J mice suggesting that aged human brains can contain pathological forms of alpha-synuclein.