Neuronal hemoglobin induces loss of dopaminergic neurons in mouse Substantia nigra, cognitive deficits and cleavage of endogenous α-synuclein

BackgroudParkinson’s disease (PD) presents the selective loss of A9 dopaminergic (DA) neurons of Substantia Nigrapars compacta(SNpc) and the presence of intracellular aggregates called Lewy bodies. α-synuclein (α-syn) species truncated at the carboxy terminal (C-terminal) accumulate in pathological inclusions and promote α-syn aggregation and toxicity.Hemoglobin (Hb) is the major oxygen carrier protein in erythrocytes. In addition, Hb is expressed in A9 DA neurons where it influences mitochondrial activity. Hb overexpression increases cells’ vulnerability in a neurochemical model of PDin vitroand forms cytoplasmic and nucleolar aggregates upon short-term overexpression in mouse SNpc.Methodsα and β-globin chains were co-expressed in DA cells of SNpcin vivoupon stereotaxic injections of an Adeno-Associated Virus isotype 9 (AAV9) and in DA iMN9D cellsin vitro.ResultsLong-term Hb over-expression in SNpc induced the loss of about 50% of DA neurons, a mild motor impairment and deficits in recognition and spatial working memory. Hb triggered the formation of endogenous α-synuclein C-terminal truncated species. Similar α-syn fragments were foundin vitroin DA iMN9D cells over-expressing α and β-globins when treated with pre-formed α-syn fibrils.ConclusionOur study positions Hb as a relevant player in PD pathogenesis for its ability to trigger DA cells’ lossin vivoand the formation of C-terminal α-synuclein fragments.