17 research outputs found
Propagated but Topologically Distributed Forebrain Neurons Expressing Alpha-Synuclein in Aged Macaques
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
Phosphorylation Modulates Clearance of Alpha-Synuclein Inclusions in a Yeast Model of Parkinson's Disease
Alpha-synuclein (aSyn) is the main component of proteinaceous inclusions known as Lewy bodies (LBs), the typical
pathological hallmark of Parkinsonâs disease (PD) and other synucleinopathies. Although aSyn is phosphorylated at low
levels under physiological conditions, it is estimated that ,90% of aSyn in LBs is phosphorylated at S129 (pS129).
Nevertheless, the significance of pS129 in the biology of aSyn and in PD pathogenesis is still controversial. Here, we
harnessed the power of budding yeast in order to assess the implications of phosphorylation on aSyn cytotoxicity,
aggregation and sub-cellular distribution. We found that aSyn is phosphorylated on S129 by endogenous kinases.
Interestingly, phosphorylation reduced aSyn toxicity and the percentage of cells with cytosolic inclusions, in comparison to
cells expressing mutant forms of aSyn (S129A or S129G) that mimic the unphosphorylated form of aSyn. Using highresolution
4D imaging and fluorescence recovery after photobleaching (FRAP) in live cells, we compared the dynamics of
WT and S129A mutant aSyn. While WT aSyn inclusions were very homogeneous, inclusions formed by S129A aSyn were
larger and showed FRAP heterogeneity. Upon blockade of aSyn expression, cells were able to clear the inclusions formed by
WT aSyn. However, this process was much slower for the inclusions formed by S129A aSyn. Interestingly, whereas the
accumulation of WT aSyn led to a marked induction of autophagy, cells expressing the S129A mutant failed to activate this
protein quality control pathway. The finding that the phosphorylation state of aSyn on S129 can alter the ability of cells to
clear aSyn inclusions provides important insight into the role that this posttranslational modification may have in the
pathogenesis of PD and other synucleinopathies, opening novel avenues for investigating the molecular basis of these
disorders and for the development of therapeutic strategies.peerReviewe