Abstract
In neurodegenerative disorders, such as Parkinson's disease (PD), alpha-synuclein (α-syn) accumulates to induce cell death and/or form a cytoplasmic inclusion called Lewy body (LB). This α-syn-related pathology is termed synucleinopathy. It remains unclear how α-syn accumulation expands during the progress of synucleinopathy in the human brain. In our study, we investigated the patterns of distribution and propagation of forebrain neurons expressing α-syn in aged macaques. It was found that the occurrence of α-syn-positive neurons proceeded topologically based on the midbrain dopamine pathways arising from the substantia nigra and the ventral tegmental area where they were primarily observed. In the nigrostriatal or mesolimbic dopamine pathway, the age-dependent increase in α-syn-positive neurons was evident in the striatum or the nucleus accumbens, respectively. Concerning the nigrostriatal pathway, a mediolateral or rostrocaudal gradient was seen in the substantia nigra or the striatum, respectively, and a compensatory increase in dopamine transporter occurred in the striatum regardless of the decreased dopamine level. In the mesocortical dopamine pathway, α-syn-positive neurons appeared in the prefrontal and then motor areas of the frontal lobe. Given that neither LB formation nor clinical phenotype manifestation was detected in any of the monkeys examined in the present study, aged macaques may be useful as a potential presymptomatic model for PD and LB-related neuropsychiatric disorders.
Highlights
Alpha-synuclein (α-syn) is a 140-amino acid protein that is localized to the presynaptic terminals and nuclei of neuronal cells, though its physiological functions remain to be known [1,2]
In Parkinson’s disease (PD), dopaminergic neuron degeneration is triggered by excess accumulation of phosphorylated α-syn, which leads to the formation of a cytoplasmic inclusion, so-called Lewy body (LB) [5,6]
The main findings were as follows: (1) α-Syn-positive neurons appeared topologically along the midbrain dopamine pathways originating in the substantia nigra and the ventral tegmental area where they were primarily located
Summary
Alpha-synuclein (α-syn) is a 140-amino acid protein that is localized to the presynaptic terminals and nuclei of neuronal cells, though its physiological functions remain to be known [1,2]. In at least part of neurodegenerative disorders, the onset of cell death is characterized by unusual accumulation of α-syn within the cytoplasm. This α-syn-related pathological condition is generally termed synucleinopathy [3]. Type 1 familial PD (PARK1) is ascribed to mutation of the SNCA gene that encodes α-syn [9]. A similar mechanism underlies type 4 familial PD (PARK4) in which the SNCA gene is triplet and α-syn production is more rapid than in PARK1 [10,11]. It is well known that the α-syn pathology is involved in familial types, and in sporadic cases of PD [12]
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