Aggregated Alpha-Synuclein Inclusions within the Nucleus Predict Impending Neuronal Cell Death in a Mouse Model of Parkinsonism

Abstract

Alpha-synuclein (aSyn) is a 14 kD protein encoded by the SNCA gene that is expressed in vertebrates and normally localizes to presynaptic terminals and the nucleus. aSyn forms pathological intracellular aggregates that typify a group of important neurodegenerative diseases called synucleinopathies. Previous work in human tissue and model systems indicates that some of these aggregates can be intranuclear, but the significance of aSyn aggregation within the nucleus is not clear. We used a mouse model that develops aggregated aSyn nuclear inclusions. Using aSyn preformed fibril injections in GFP-tagged aSyn transgenic mice, we were able to induce the formation of nuclear aSyn inclusions and study their properties in fixed tissue and in vivo using multiphoton microscopy. In addition, we analyzed human synucleinopathy patient tissue to better understand this pathology. Our data demonstrate that nuclear aSyn inclusions may form through the transmission of aSyn between neurons, and these intranuclear aggregates bear the hallmarks of cytoplasmic Lewy pathology. Neuronal nuclear aSyn inclusions can form rod-like structures that do not contain actin, excluding them from being previously described nuclear actin rods. Longitudinal, in vivo multiphoton imaging indicates that certain morphologies of neuronal nuclear aSyn inclusions predict cell death within 14 days. Human multiple system atrophy cases contain neurons and glia with similar nuclear inclusions, but we were unable to detect such inclusions in Lewy body dementia cases. This study suggests that the dysregulation of a nuclear aSyn function associated with nuclear inclusion formation could play a role in the forms of neurodegeneration associated with synucleinopathy.

Nuclear α-Synuclein-Derived Cytotoxic Effect via Altered Ribosomal RNA Processing in Primary Mouse Embryonic Fibroblasts

“…Several studies have reported that the presence of αSyn in the nucleus of cells may underlie αSyn-derived neurodegeneration [6][7][8][9]. We demonstrated that the nucleus-localized αSyn promoted similar cytotoxicity as described in previous studies [7][8][9], and was related to the abnormal rRNA processing and elevated ribosomal protein in this study (Figure 8). Thus, the neurotoxicity of nuclear αSyn might be mediated via ribosomal biogenesis, and the accumulated cytosolic αSyn would propagate the spread of alpha-synucleinopathy and neuroinflammation by the disruption of autophagy-lysosomal degradation pathway.…”

“…αSyn is a major component of Lewy bodies (LB) and Lewy neurites (LN). Most αSyn aggregating in vitro in LB and LN was found in the cytoplasm; however, some αSyn was localized in the nucleus [6][7][8][9]. In previous studies, nuclear αSyn manifested toxic effects on cells [7].…”

Cerebral Microvascular Injury Induced by Lag3‐Dependent α‐Synuclein Fibril Endocytosis Exacerbates Cognitive Impairment in a Mouse Model of α‐Synucleinopathies

“…It has been reported that cell‐to‐cell transmission of α ‐Syn aggregates is associated with apoptosis and loss of nuclear membrane integrity; the α ‐Syn aggregates released during cell decomposition can be endocytosed by surrounding cells, causing α ‐Syn to spread to neighboring cells, implying that the speed at which α ‐Syn aggregates are released upon cell death and the fibrotic degree of these released α ‐Syn aggregates determine the extent of α ‐Syn transmission. [ 40 ] These findings prompted us to focus on the effects of α ‐Syn fibrils on cerebral microvascular cell death. As shown in Sections 2.7 and 2.8 , our results provide evidence supporting that Lag3‐dependent α ‐synuclein fibrils endocytosis can induce PAR‐driven cell death in BMVECs.…”

Alpha-Synuclein Contribution to Neuronal and Glial Damage in Parkinson’s Disease

“…pS129 facilitates αSyn nuclear import and retention, which disrupts DNA stabilization and repair [ 226 , 227 , 228 ]. Interestingly, inoculation of αSyn pre-formed fibrils (PFF) into the mouse brain leads to the formation of the pS129-αSyn inclusions, subsequent spreading across neurons, and neuronal death [ 229 ]. The above results indicate the potential role of pS129-αSyn and nuclear dysregulation in driving α-synucleinopathies.…”